This is another of a series of blog posts relating to Alzheimer’s Disease (AD). The earlier posts included New views of Alzheimer’s disease and new approaches to treating it, The social cost of Alzheimer’s disease and late-life dementia, Diet and cognition, Warding off Alzheimer’s Disease and things in my diet, and a short post Deconstructing Alzheimer’s Disease – role of mitochondria. This update picks up on some topics introduced in the earlier entries, particularly in the May 2010 blog entry Alzheimer’s Disease research update and in the July 2010 blog entry Alzheimer’s disease studies validate anti-aging firewalls suggestions. And I discuss a few key new topics as well.
A short primer on Beta-amyloid and Tau tangles
The major mechanisms of AD pathology that have been studied intensely over the recent years are the intercellular accumulation of beta-amyloid protein and the intra-cellular buildup of tau tangles. As background, I briefly characterize both of these phenomena which characterize AD.“Amyloid beta (Aβ or Abeta or beta amyloid) is a peptide of 36–43 amino acids that appears to be the main constituent of amyloid plaques in the brains of Alzheimer’s disease patients. Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis, a muscle disease. Aβ also forms aggregates coating cerebral blood vessels in cerebral amyloid angiopathy(ref).” Generally, the amount of amyloid plaques in the brain is used as a measurement of the severity of AD.
Processing of the amyloid precursor protein
Tau tangles [also known as Neurofibrillary tangles (NFTs)] are tangles of misfolded tau protein that occur in nerve cells in AD patients. Tau tangles are “aggregates of hyperphosphorylation tau that are most commonly known as a primary marker of Alzheimer’s Disease. Their presence is also found in numerous other diseases known as Tauopathies(ref).” Tau proteins play important roles in healthy nerve tissues. The normal function of tau is to support microtubules, physical scaffold structures within nerve cells. “Tau proteins are proteins that stabilize microtubules. They are abundant in neurons in the central nervous system and are less common elsewhere. When tau proteins are defective, and no longer stabilize microtubules properly, they can result in dementias, such as Alzheimer’s disease(ref).” The presence of amyloid beta is known to lead to tau tangles. “The pathologic hallmarks of Alzheimer’s disease (AD) include senile plaque, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration. Senile plaque and NFTs are formed by accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, respectively(ref).”
For a number of years much of not most research on AD therapies was focused on strategies for prevention or removal of Aβ from brain tissues. Later, prevention or removal of tau tangles became another focus of research. And more-recently there has been concern with how aberrant microglial activation might be an upstream cause of both Aβ plaques and tau tangles.
My coverage of topics here is necessarily selective. Other important research related to AD is discussed in earlier blog entries accessible via the above links.
Some properties of amyloid beta
– – Amyloid beta may not actually be responsible for the pathology of AD. “The “amyloid hypothesis”, that the plaques are responsible for the pathology of Alzheimer’s disease, is accepted by the majority of researchers but is by no means conclusively established. Intra-cellular deposits of tau protein are also seen in the disease, and may also be implicated. The oligomers that form on the amyloid pathway, rather than the mature fibrils, may be the cytotoxic species. – – An alternative hypothesis is that amyloid oligomers rather than plaques are responsible for the disease. Mice that are genetically engineered to express oligomers but not plaques (APPE693Q) develop the disease. Furthermore mice that are in addition engineered to convert oligomers into plaques (APPE693Q X PS1ΔE9), are no more impaired than the oligomer only mice.(ref)” “Moreover, the recent failure of Aβ lowering agents, such as tramiprosate (11) and flurbiprofen (2) in phase III clinical trials, suggests that there is a need to pursue other therapeutic approaches, including those that reduce the levels of pathological tau(ref).”
– Plentiful amyloid beta plaques can be found in the brains of dead patients who showed no signs of AD or dementia. “– Most, if not all, people have amyloid plaques in the brain years before they develop clinical symptoms of Alzheimer’s. — “It’s not uncommon for us to determine that an older person is fully intact mentally only to find the presence of substantial Alzheimer’s pathology on examining that person’s brain after death,” says John C. Morris, M.D., the Harvey A. and Dorismae Friedman Distinguished Professor of Neurology and director of the ADRC and of the Harvey A. Friedman Center for Aging. “We suspect that Alzheimer lesions may be present in the brain long before we can detect any clinical symptoms.”(ref)” Again, the culprit may be certain oligomers, as indicated in certain of the citations listed below.
– – Amyloid beta plaques can show up in a brain in only a day with AD neuronal changes shortly following. As reported in a 2009 Science Daily article Alzheimer’s-Associated Plaques Can Form In A Day, And Alzheimer’s Symptoms Soon Follow “– The amyloid plaques found in the brains of Alzheimer’s disease patients may form much more rapidly than previously expected. Using an advanced microscopic imaging technique to examine brain tissue in mouse models of the devastating neurological disorder, researchers from the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), working with colleagues from Washington University School of Medicine, find that plaques can develop in as little as a day and that Alzheimer’s-associated neuronal changes appear soon afterwards. — Although plaques formed rarely, they could appear as little as 24 hours after a previous plaque-free image was taken. The new plaques were similar in appearance to those seen in the brains of Alzheimer’s patients and in the mouse models, and subsequent imaging showed little change in the size of plaques once they had formed. – — Examining neurons adjacent to plaques showed that the kind of changes associated with Alzheimer’s — distortions in the projections through which neuronal signals pass — appear rapidly and approach maximum effect within five days. — “These results confirm the suspicion we’ve had that plaques are a primary event in the glial and neuronal changes that underlie Alzheimer’s dementia.””
AD and the Sirtuin SIRT1
In the May 2010 blog post on AD, the first Section is entitled SIRT1 and Resveratrol and Alzheimer’s Disease. There, I cite preliminary evidence for a hypothesis that activation of the SIRT1 gene, such as possibly by resveratrol, could be a preventative or therapeutic strategy against AD. I wrote “I discussed how some researchers think activation of SIRT1 might confer a strong therapeutic effect for control of Alzheimer’s disease. Several review articles published in the last couple of years articulate that hypothesis and suggest a potential role for resveratrol in controlling AD. These articles include the March 2010 e-publication Resveratrol as a Therapeutic Agent for Neurodegenerative Diseases, the 2009 publication Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection and the 2008 publication Modulation of sirtuins: new targets for antiageing.”
Since writing the previous blogs on AD, a new publication has appeared, SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10, one that reveals a mechanism through which SIRT1 activation combats AD. “A hallmark of Alzheimer’s disease (AD) is the accumulation of plaques of Aβ 1 40 and 1 42 peptides, which result from the sequential cleavage of APP by the β and -secretases. The production of Aβ peptides is avoided by alternate cleavage of APP by the α and -secretases. Here we show that production of β-amyloid and plaques in a mouse model of AD are reduced by overexpressing the NAD-dependent deacetylase SIRT1 in brain, and are increased by knocking out SIRT1 in brain. SIRT1 directly activates the transcription of the gene encoding the α-secretase, ADAM10. SIRT1 deacetylates and coactivates the retinoic acid receptor β, a known regulator of ADAM10 transcription. ADAM10 activation by SIRT1 also induces the Notch pathway, which is known to repair neuronal damage in the brain. Our findings indicate SIRT1 activation is a viable strategy to combat AD and perhaps other neurodegenerative diseases.”
The work characterized in this publication is discussed in a Science Daily article Gene Linked to Aging Also Linked to Alzheimer’s. “ScienceDaily (July 22, 2010) — MIT biologists report that they have discovered the first link between the amyloid plaques that form in the brains of Alzheimer’s patients and a gene previously implicated in the aging process, SIRT1. — The researchers found that SIRT1 appears to control production of the devastating protein fragments, termed A-beta peptides, that make up amyloid plaques.” [As described above by inducing cleavage of APP by the α and -secretases instead of by β and -secretases, yielding harmless protein fragments instead of Amyloid beta.] “They also showed that in mice engineered to develop Alzheimer’s plaques and symptoms, learning and memory deficits were improved when SIRT1 was overproduced in the brain, and exacerbated when SIRT1 was deleted.”
Potential control of AD via inhibition of 5-lipoxygenase
The November 2010 publication 5-lipoxygenase as an endogenous modulator of amyloid beta formation in vivo suggests a mechanism involved in the creation of beta amyloid plaques. “Objective : The 5-lipoxygenase (5-LO) enzymatic pathway is widely distributed within the central nervous system, and is upregulated in Alzheimer’s disease. However, the mechanism whereby it may influence the disease pathogenesis remains elusive. – Methods: We evaluated the molecular mechanism by which 5-LO regulates amyloid β (Aβ) formation in vitro and in vivo by pharmacological and genetic approaches.– Results: Here we show that 5-LO regulates the formation of Aβ by activating the cAMP-response element binding protein (CREB), which in turn increases transcription of the γ-secretase complex. Preventing CREB activation by pharmacologic inhibition or dominant negative mutants blocks the 5-LO-dependent elevation of Aβ formation and the increase of γ-secretase mRNA and protein levels. Moreover, 5-LO targeted gene disruption or its in vivo selective pharmacological inhibition results in a significant reduction of Aβ, CREB and γ-secretase levels. – Interpretation: These data establish a novel functional role for 5-LO in regulating endogenous formation of Aβ levels in the central nervous system. Thus, 5-LO pharmacological inhibition may be beneficial in the treatment and prevention of Alzheimer’s disease.”
Additional insight into the significance of this finding is contained in a 2010 Science Daily article Modulating a Protein in the Brain Could Help Control Alzheimer’s Disease. “According to Domenico Praticò, an associate professor of pharmacology in Temple’s School of Medicine and the study’s lead researcher, the 5-Lipoxygenase enzyme is found in abundance mainly in the region of the brain, the hippocampus, involved in memory. — Praticò and his team discovered that 5-lipoxygenase, which unlike most proteins in the brain increases its levels during the aging process. It also controls the activation state of another protein, called gamma secretase, a complex of four elements which are necessary and responsible for the final production of the amyloid beta, a peptide that when produced in excess deposits and forms plaques in the brain. — “What we found was 5-lipoxygenase regulates and controls the amount of total amyloid beta produced in the brain,” said Praticò. “With aging, the more 5-lipoxygenase you have the more amyloid beta you’re going to produce. This will translate into a higher risk to develop full Alzheimer’s.” — A previous study by Praticò, in which researchers crossed a mouse model of Alzheimer’s with a mouse that did not genetically feature 5-lipoxygenase, demonstrated that a lack of this enzyme protein alone can reduce the amount of disease in the brain by up to half. — “It has been known for years that the 5-lipoxygenase is an important protein in other areas of the body, such as the lung, but nobody really cared about its role in the brain,” he said. “Based on some previously know information, we questioned whether this enzyme was a primary or secondary player in the development of Alzheimer’s. What we found was a new primary role for an old enzyme.””
The significance of this finding is that drugs that inhibit 5-lipoxygenase are already on the market and could possibly be used to control AD. Continuing, “Praticò said that the key in the process was 5-lipoxygenase’s direct control over the gamma secretase, the only source of amyloid beta in the brain. “If you can modulate this enzyme easily, then you can control the amount of total amyloid beta that is produced by the gamma secretase in the brain, thus controlling the amount of Alzheimer’s disease.” — Praticò said that armed with new information, new therapies could be developed to block the increase of 5-lipoxygenase levels in the aging brain, which would in turn prevent the formation of amyloid beta. He said that there are several FDA-approved 5-lipoxygenase inhibitors currently being used for the treatment of asthma, and that the Temple researchers tested some of these inhibitors in the lab against the production of amyloid beta with initial positive results. — “These drugs are already on the market, they’re inexpensive and, most importantly, they are already FDA-approved, so you wouldn’t need to go through an intense drug discovery process,” said Praticò. “So you could quickly begin a clinical trial to determine if there is a new application for an old drug against a disease where there is currently nothing(ref).”
Microglial senescence and AD
In my February 2010 blog entry New views of Alzheimer’s disease and new approaches to treating it, I cited evidence for the hypothesis that microglial cell senescence is probably a fundamental cause for AD, a cause upstream of beta amyloid plaque production and the setting in of tau tangles. There seems to be accumulating evidence for this hypothesis.
First of all, activation of non-senescent microglia appears to play a positive role at least in the early stages of AD. The 2011 publication Determination of Spatial and Temporal Distribution of Microglia by 230nm-High-Resolution, High-Throughput Automated Analysis Reveals Different Amyloid Plaque Populations in an APP/PS1 Mouse Model of Alzheimer’s Disease reports “One early and prominent pathologic feature of Alzheimer’s disease (AD) is the appearance of activated microglia in the vicinity of developing β-amyloid deposits. However, the precise role of microglia during the course of AD is still under discussion. Microglia have been reported to degrade and clear β-amyloid, but they also can exert deleterious effects due to overwhelming inflammatory reactions. Here, we demonstrate the occurrence of developing plaque populations with distinct amounts of associated microglia using time-dependent analyses of plaque morphology and the spatial distribution of microglia in an APP/PS1 mouse model. In addition to a population of larger plaques (>700µm(2)) that are occupied by a moderate contingent of microglial cells across the course of aging, a second type of small β-amyloid deposits develops (≤400µm(2)) in which the plaque core is enveloped by a relatively large number of microglia. Our analyses indicate that microglia are strongly activated early in the emergence of senile plaques, but that activation is diminished in the later stages of plaque evolution (>150 days). These findings support the view that microglia serve to restrict the growth of senile plaques, and do so in a way that minimizes local inflammatory damage to other components of the brain.” The 2011 publication Mechanism mediating oligomeric Aβ clearance by naïve primary microglia provides insight into how microglia are involved in the clearance of Aβ and their roles in the early stages of AD.
Second, it appears that with aging microglia lose their capability to get rid of beta amyloid via phagocytosis. A March 2011 publication supports this case: Microglia Demonstrate Age-Dependent Interaction with Amyloid-β Fibrils. “Alzheimer’s disease (AD) is an age-associated disease characterized by increased accumulation of extracellular amyloid-β (Aβ) plaques within the brain. Histological examination has also revealed profound microglial activation in diseased brains often in association with these fibrillar peptide aggregates. The paradoxical presence of increased, reactive microglia yet accumulating extracellular debris suggests that these cells may be phagocytically compromised during disease. Prior work has demonstrated that primary microglia from adult mice are unable to phagocytose fibrillar Aβ1-42 in vitro when compared to microglia cultured from early postnatal animals. These data suggest that microglia undergo an age-associated decrease in microglial ability to interact with Aβ fibrils. In order to better define a temporal profile of microglia-Aβ interaction, acutely isolated, rather than cultured, microglia from 2 month, 6 month, and postnatal day 0 C57BL/6 mice were compared. Postnatal day 0 microglia demonstrated a CD47 dependent ability to phagocytose Aβ fibrils that was lost by 6 months. This corresponded with the ability of postnatal day 0 but not adult microglia to decrease Aβ immunoreactive plaque load from AD sections in vitro. In spite of limited Aβ uptake ability, adult microglia had functional phagocytic uptake of bacterial bioparticles and demonstrated the ability to adhere to both Aβ plaques and in vitro fibrillized Aβ. These data demonstrate a temporal profile of specifically Aβ-microglia interaction with a critical developmental period at 6 months in which cells remain able to interact with Aβ fibrils but lose their ability to phagocytose it.”
The 2011 publication γ-Secretase component presenilin is important for microglia β-amyloid clearance suggests another important role for γ-secretase beyond that already outlined above. “We suggest for the first time, a dual role for γ-secretase in Alzheimer’s disease. One role is the cleavage of the amyloid precursor protein for pathologic β-amyloid production and the other is to regulate microglia activity that is important for clearing neurotoxic β-amyloid deposits. Further studies of γ-secretase-mediated cellular pathways in microglia may provide useful insights into the development of Alzheimer’s disease and other neurodegenerative diseases, providing future avenues for therapeutic intervention.”
If someone were to tell me last week that smoking pot could help ward off Alzheimer’s Disease by affecting microglial activation, my response would likely have been “What have you been smoking lately?” That would have been my reaction before I found this February 2011 publication Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimers’ disease. “Microglial activation is an invariant feature of Alzheimer’s disease (AD). Interestingly cannabinoids are neuroprotective by preventing β-amyloid (Aβ) induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behaviour and cytokine expression following Aβ intraventricular administration to mice, – Interestingly cannabinoids are neuroprotective by preventing β-amyloid (Aβ) induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study we
compared the effects of CBD with those of other cannabinoids on microglial cell
functions in vitro and on learning behaviour and cytokine expression following
Aβ intraventricular administration to mice. CBD, WIN 55,212-2 (WIN), a mixed
CB(1)/CB(2) agonist, and JWH-133 (JWH), a CB(2) selective agonist,
concentration-dependently decreased ATP-induced (400 [micro]M) increase in
intracellular calcium ([Ca(2+)](i)) in cultured N13 microglial cells and in rat
primary microglia. In contrast HU-308 (HU), another CB(2) agonist, was without
effect. Cannabinoid and adenosine A(2A) receptors may be involved in the CBD
action. CBD and WIN-promoted primary microglia migration was blocked by CB(1)
and/or CB(2) antagonists. JWH and HU-induced migration was blocked by a CB(2)
antagonist only. All the cannabinoids decreased LPS-induced nitrite generation,
which was insensitive to cannabinoid antagonism. Finally both CBD and WIN,
following subchronic administration for three weeks.”
“Antioxidant activity has been reported to be a general property of the phenolic components of marijuana. Unlike Δ9-THC, cannabidiol can be administered at relatively high doses without undesired toxic or psychological effects.1(ref)” The March 2011 publication Caspase signalling controls microglia activation and neurotoxicity implicates caspases in microglial activation and therefore in AD. “Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. — We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson’s disease (PD) and the frontal cortex of individuals with Alzheimer’s disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.”
To a considerable extent, aging-related neurodegenerative diseases appear to depend on the same underlying mechanisms
The previously-cited publication describes how caspase-induced microglial activation could be an underlying cause of both AD and Parkinson’s Disease. Another March 2011 publication brings multiple sclerosis under the same umbrella: Mechanisms of neurodegeneration shared between multiple sclerosis and Alzheimer’s disease. “Multiple sclerosis and Alzheimer’s disease are fundamentally different diseases. However, recent data suggest that certain mechanisms of neurodegeneration may be shared between the two diseases. Inflammation drives the disease in multiple sclerosis. It is also present in Alzheimer’s disease lesions, where it may have dual functions in amyloid clearance as well as in the propagation of neurodegeneration. In both diseases, degeneration of neurons, axons, and synapses occur on the background of profound mitochondrial injury. Reactive oxygen and nitric oxide intermediates are major candidates for the induction of mitochondrial injury. Radicals are produced through the induction of the respiratory burst in activated microglia, which are present in the lesions of both diseases. In addition, liberation of toxic iron from intracellular stores may augment radical formation. Finally reactive oxygen species are also produced in the course of mitochondrial injury itself. Anti-oxidant and mitochondria protective therapeutic strategies may be beneficial both in multiple sclerosis and Alzheimer’s disease in particular in early stages of the disease.”
The role of mitochondrial damage in AD is another topic of relevant in the chain of events leading to full-blown AD. I touched lightly on this in the early blog entry Deconstructing Alzheimer’s Disease – role of mitochondria. Another 2011 publication amplifies on the role of microglial activation in Parkinson’s Disease as well as in AD: CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease. “The inflammatory response in the brain is tightly regulated at multiple levels. One form of immune regulation occurs via neurons. Fractalkine (CX3CL1), produced by neurons, suppresses the activation of microglia. CX3CL1 is constitutively expressed. — As hypothesized, CX3CL1 was able to suppress this microglia activation. The reduced microglia activation was found to be neuroprotective as the CX3CL1 treated rats had a smaller lesion volume in the striatum and importantly significantly fewer neurons were lost in the CX3CL1 treated rats. — These findings demonstrated that CX3CL1 plays a neuroprotective role in 6-OHDA-induced dopaminergic lesion and it might be an effective therapeutic target for many neurodegenerative diseases, including Parkinson disease and Alzheimer disease, where inflammation plays an important role.”
Other recent publications relating microglial activation to AD pathology
* The increased density of p38 mitogen-activated protein kinase-immunoreactive microglia in the sensorimotor cortex of aged TgCRND8 mice is associated predominantly with smaller dense-core amyloid plaques (Feb 2011),
* Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia (Feb 2011), and
* ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels (Feb 2011).
Exercise and tau AD pathology
The2011 publication Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23 concludes “In this study, the tau-transgenic (Tg) mouse, Tg-NSE/htau23, which over expresses human Tau23 in its brain, was subjected to chronic exercise for 3months, from 16months of age. The brains of Tg mice exhibited increased immunoreactivity and active morphological changes in GFAP (astrocyte marker) and MAC-1 (microglia marker) expression in an age-dependent manner. To identify the effects of chronic exercise on gliosis, the exercised Tg mice groups were treadmill run at a speed of 12m/min (intermediate exercise group) or 19m/min (high exercise group) for 1h/day and 5days/week during the 3month period. The neuroinflammatory response characterized by activated astroglia and microglia was significantly repressed in the exercised Tg mice in an exercise intensity-dependent manner. In parallel, chronic exercise in Tg mice reduced the increased expression of TNF-α, IL-6, IL-1β, COX-2, and iNOS. Consistently with these changes, the levels of phospho-p38 and phospho-ERK were markedly downregulated in the brain of Tg mice after exercise. In addition, nuclear NF-κB activity was profoundly reduced after chronic exercise in an exercise intensity-dependent manner. These findings suggest that chronic endurance exercise may alleviate neuroinflammation in the Tau pathology of Alzheimer’s disease.”
At least some symptoms of AD can be reversed
A November 2010 publication CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer’s disease reports “Here we show that amyloid-β (Aβ) accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in Aβ and tau pathology, and instead are linked to an increased level of brain-derived neurotrophic factor. The resulting data suggest that Aβ-induced learning and memory deficits are mediated by alterations in CREB function, based on the finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Therefore, increasing CBP expression in adult brains may be a valid therapeutic approach not only for AD, but also for various brain disorders characterized by alterations in immediate early genes, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases.”
Below I discuss how curcumin could possibly contribute to normalization of CREB activity.
Inhibition or removal of tau tangles by manipulation of Hsp70 and Hsp27 chaperone proteins
The chaperone proteins Hsp70 and Hsp27 apparently can play roles in preventing or getting rid of tau tangles in brains affected by AD. This should not be surprising since tau tangles are the results of misfolded proteins and the key role of these chaperone proteins is to assure proper protein folding. As I pointed out in the blog entry HSP70 to the rescue, “ While you are at it, by the way, you might want to check out The Incorrect protein folding theory of aging discussed in my treatise. The basic notion is that stress often leads to the misfolding of proteins, a process that can accelerate with age creating dysfunctional conditions and vulnerability to a number of diseases.
Misfolded proteins cannot perform their intended functions and can create active mischief. In a nutshell, the role of the HSP70 heat shock proteins is to mobilize when large numbers of misfolded proteins show up due to stress, and to fold them up properly again. So, HSP70 proteins play important roles in health maintenance and possibly also in longevity.” As it turns out, manipulation of both Hsp70 and Hsp27 can indeed play a role in clearance of tau tangles, but how and when they can be manipulated to do this is fairly complicated.
The 2009 publication Chemical Manipulation of Hsp70 ATPase Activity Regulates Tau Stability relates “Alzheimer’s disease and other tauopathies have recently been clustered with a group of nervous system disorders termed protein misfolding diseases. The common element established between these disorders is their requirement for processing by the chaperone complex. It is now clear that the individual components of the chaperone system, such as Hsp70 and Hsp90, exist in an intricate signaling network that exerts pleiotropic effects on a host of substrates. Therefore, we have endeavored to identify new compounds that can specifically regulate individual components of the chaperone family. Here, we hypothesized that chemical manipulation of Hsp70 ATPase activity, a target that has not previously been pursued, could illuminate a new pathway toward chaperone-based therapies.– Using a newly developed high-throughput screening system, we identified inhibitors and activators of Hsp70 enzymatic activity. Inhibitors led to rapid proteasome-dependent tau degradation in a cell-based model. Conversely, Hsp70 activators preserved tau levels in the same system. Hsp70 inhibition did not result in general protein degradation, nor did it induce a heat shock response. We also found that inhibiting Hsp70 ATPase activity after increasing its expression levels facilitated tau degradation at lower doses, suggesting that we
can combine genetic and pharmacologic manipulation of Hsp70 to control the fate
of bound substrates. Disease relevance of this strategy was further established
when tau levels were rapidly and substantially reduced in brain tissue from tau
transgenic mice. These findings reveal an entirely novel path toward therapeutic
intervention of tauopathies by inhibition of the previously untargeted ATPase
activity of Hsp70.”
In other words the opposite of what was expected occurred. Instead of Hsp70 working to properly refold proteins in tau tangles, inhibition of Hsp70 worked to get rid of the tau tangles.
Clarification of this surprising result is provided in the Science Daily article Protein Inhibitor Helps Rid Brain Of Toxic Tau Protein. “The USF researchers originally thought activating Hsp70 would direct the chaperone protein to decrease the tau gone bad — preventing tau from stacking up into tangles inside cells involved in memory and destroying them. But instead of restoring tau to its normal supportive function, activating Hsp70 actually led to tau’s preservation and even more accumulation, Dickey said. “Basically we think the chaperone binds to the tau, and somehow in the process of trying to fix things decides to keep holding onto tau when it shouldn’t. So, activating Hsp70 is not necessarily what we want to do; we ultimately want to inhibit Hsp70 to promote the release or clearance of tau …to kill the bad tau.”
The December 2010 publication Phosphorylation Dynamics Regulate Hsp27-Mediated Rescue of Neuronal Plasticity Deficits in Tau Transgenic Mice relates “Molecular chaperones regulate the aggregation of a number of proteins that pathologically misfold and accumulate in neurodegenerative diseases. Identifying ways to manipulate these proteins in disease models is an area of intense investigation; however, the translation of these results to the mammalian brain has progressed more slowly. In this study, we investigated the ability of one of these chaperones, heat shock protein 27 (Hsp27), to modulate tau dynamics. Recombinant wild-type Hsp27 and a genetically altered version of Hsp27 that is perpetually pseudo-phosphorylated (3×S/D) were generated. Both Hsp27 variants interacted with tau, and atomic force microscopy and dynamic light scattering showed that both variants also prevented tau filament formation. However, extrinsic genetic delivery of these two Hsp27 variants to tau transgenic mice using adeno-associated viral particles showed that wild-type Hsp27 reduced neuronal tau levels, whereas 3×S/D Hsp27 was associated with increased tau levels. Moreover, rapid decay in hippocampal long-term potentiation (LTP) intrinsic to this tau transgenic model was rescued by wild-type Hsp27 overexpression but not by 3×S/D Hsp27. Because the 3×S/D Hsp27 mutant cannot cycle between phosphorylated and dephosphorylated states, we can conclude that Hsp27 must be functionally dynamic to facilitate tau clearance from the brain and rescue LTP; however, when this property is compromised, Hsp27 may actually facilitate accumulation of soluble tau intermediates.”
The December 2010 Science Daily article Dynamics of Chaperone Protein Critical in Rescuing Brains of Alzheimer’s Mice from Neuron Damage explains further “The researchers concluded that Hsp27 must be able to fluctuate between activated and de-activated states to succeed at clearing abnormal tau, thus preventing the protein from sticking together and building up excessively in the brain. In addition, Hsp27 can only be effective in helping maintain healthy tau turnover if the chaperone protein interacts with tau while it’s still soluble — before tau has developed into solid nerve-killing tangles. The chaperone protein cannot disrupt already formed tau tangles. — “In some circumstances, the activated chaperone protein may help stabilize and recycle tau, restoring the protein so it can do its normal job of supporting nerve cell structure,” Dr. Dickey said. “But when tau has become abnormally folded, activated Hsp27 may actually hold onto the bad tau without letting go, subverting tau’s release or clearance from the brain. In that case, it would be better to inhibit or deactivate Hsp27 to get rid of the tau.””
Clearance of tau protein via manipulation of chaperone proteins continues to be an active area of AD research. Again, I remain skeptical as to the prospects for such an approach to lead to a successful AD therapy.
Curcumin and AD
Relative to the last-mentioned citation, in the August 2010 blog entry Neurogenesis, curcumin and longevity I described how the dietary supplement curcumin can contribute to increased levels of brain-derived neurotrophic factor (BDNF) and normalizing CREB. “The 2005 publication Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition relates to the effects of but not the process of neurogenesis in rat’s brains. “– Here, — we have examined the possibility that dietary curcumin may favor the injured brain by interacting with molecular mechanisms that maintain synaptic plasticity and cognition. The analysis was focused on the BDNF system based on its action on synaptic plasticity and cognition by modulating synapsin I and CREB. — Supplementation of curcumin in the diet dramatically reduced oxidative damage and normalized levels of BDNF, synapsin I, and CREB that had been altered after TBI. Furthermore, curcumin supplementation counteracted the cognitive impairment caused by TBI. These results are in agreement with previous evidence, showing that oxidative stress can affect the injured brain by acting through the BDNF system to affect synaptic plasticity and cognition.”
While this research was reported in the context of traumatic brain injury (TBI), to the extent that curcumin can restore levels of BDNF and CREB to normal, it is possible that its consumption could improve the symptoms of AD. There is a growing literature on the potential role of curcumin as an AD therapy. But how does it work? I mention here only the 2011 publication Curcuminoid Binds to Amyloid-β1-42 Oligomer and Fibril. “Studies of Alzheimer’s disease (AD) strongly support the hypothesis that amyloid-β (Aβ) deposition in the brain is the initiating event in the progression of AD. Aβ peptides easily form long insoluble amyloid fibrils, which accumulate in deposits known as senile plaques. On the other hand, recent work indicated that soluble Aβ oligomers, rather than monomers or insoluble Aβ fibrils, might be responsible for neuronal and synaptic dysfunction in AD. Curcumin, a low molecular weight yellow-orange pigment derived from the turmeric plant, has shown therapeutic effects in transgenic mouse models of AD. However, it remains unclear whether curcumin interacts directly with the Aβ oligomers. This study investigated any interaction between curcumin and Aβ oligomers such as globulomer and Aβ-derived diffusible ligand (ADDL). Globulomer was observed as a cluster of spherical structures by electron microscopic analysis, and ADDL was also detected as small spherical structures. Fluorescence analysis revealed a significant increase in the fluorescence of curcumin when reacted with both oligomers. Furthermore quartz crystal microbalance analysis showed significant frequency decreases in oligomer-immobilized electrodes following the addition of curcumin. These results strongly suggested that curcumin binds to Aβ oligomers and to Aβ fibrils. The association of curcumin with Aβ oligomers may contribute to the therapeutic effect on AD. Based on these findings, curcumin could provide the basis of a novel concept in AD therapies targeting Aβ oligomers.”
As is generally the case when I write about complex topics, my coverage of subtopics here is necessarily partial and focused. A search in the government database of research publications pubmed.org using the term “Alzheimer’s” reveals 30,922 publications.
Wrapping it up
The above publications together suggest a rich handful of observations including:
1. I wonder if trying to treat AD by prevention or removal of amyloid beta, or prevention or removal of tau tangles for that matter, is like trying to treat smallpox or measles as skin diseases. I believe there are upstream causes of AD having to do with aging and that both amyloid beta and tau tangles are consequential downstream phenomena. No wonder that the vast efforts to treat AD based on getting rid of Aβ or tau have so far come to naught.
2. Properties of microglia are definitely age and senescence-related lending credence to seeing microglial senescence as an underlying cause of AD.
3. Activation of aged microglia could underlie other age-related neurodegenerative diseases besides Alzheimer’s Disease including Parkinson’s Disease and multiple sclerosis.
4. Suggested in my treatise as theories of aging, Oxidative Damage and Mitochondrial Damage act as mechanisms in the aetiology of AD, probably as downstream consequences of more basic causes such as microglial senescence.
5. Regular exercise leads to decreased activation of microglia and astroglia in certain tau+ transgenic mouse strains, and decreased neuroinflammation. This suggests that regular exercise may be protective of those already experiencing tau pathology in AD.
6. Evidence continues to emerge supporting the power of curcumin for prevention or treatment of AD as well as a number of other neurological
7. In a series of blog entries including the recent one Aging and diseases, I have repeated an opinion that for diseases if aging including AD, there is unlikely to be any basic cure that does not address the processes of aging themselves. Microglial senescence is such a process. The increase of 5-lipoxygenase with age is another of many such processes affecting AD. What I have seen in the above-reviewed AD research has served to reinforce that
FROM TIME TO TIME, THIS BLOG DISCUSSES DISEASE PROCESSES. THE INTENTION OF THOSE DISCUSSIONS IS TO CONVEY CURRENT RESEARCH FINDINGS AND OPINIONS, NOT TO GIVE MEDICAL ADVICE. THE INFORMATION IN POSTS IN THIS BLOG IS NOT A SUBSTITUTE FOR A LICENSED PHYSICIAN’S MEDICAL ADVICE. IF ANY ADVICE, OPINIONS, OR INSTRUCTIONS HEREIN CONFLICT WITH THAT OF A TREATING LICENSED PHYSICIAN, DEFER TO THE OPINION OF THE PHYSICIAN. THIS INFORMATION IS INTENDED FOR PEOPLE IN GOOD HEALTH. IT IS THE READER’S RESPONSIBILITY TO KNOW HIS OR HER MEDICAL HISTORY AND ENSURE THAT ACTIONS OR SUPPLEMENTS HE OR SHE TAKES DO NOT CREATE AN ADVERSE REACTION.
The presence of amyloid beta is known to lead to tau tangles. â€œThe pathologic hallmarks of Alzheimerâ€™s disease (AD) include senile plaque, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration. Senile plaque and NFTs are formed by accumulation of amyloid-Î² (AÎ²) and hyperphosphorylated tau, respectively(ref).â€
Just to make sure: the quote says that senile plaque is formed by A-beta, and NFTs are formed by hyperphosphorylated tau, but not that A-beta leads to tau tangles.
Great blog, keep it up! 🙂
I think the sequence is this: Senile plaques show up as an identifying mark of AD consisting of amyloid-Î². Following or coincident with appearance of the plaques and possibly a consequence of the plaques, the tau tangles appear which consist of hyperphosphorylated tau. So, in the usual viewpoint of AD, the amyloid-Î² leads indirectly to the tau tangles.
I didn’t see anything new here regarding AD being essentially diabetes type III. But for reference purposes, one way to halt AD is by ingesting medium-chain triglycerides from virgin coconut oil. Since the brain is glucose/insulin resistant in diabetes type III, providing ketone bodies is the only way it’ll absorb any energy.
I think you will like to read the article.
I got very very curious about the last post Diabetes type 3 and coconut oil.
Public release date: 3-Mar-2011
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Contact: Mika Ono
Scripps Research Institute
Scripps Research study points to liver, not brain, as origin of Alzheimer’s plaques
Results could lead to new strategies for prevention and therapy
LA JOLLA, CA â€“ March 3, 2011 â€“ Unexpected results from a Scripps Research Institute and ModGene, LLC study could completely alter scientists’ ideas about Alzheimer’s diseaseâ€”pointing to the liver instead of the brain as the source of the “amyloid” that deposits as brain plaques associated with this devastating condition. The findings could offer a relatively simple approach for Alzheimer’s prevention and treatment.
The study was published online today in The Journal of Neuroscience Research.
In the study, the scientists used a mouse model for Alzheimer’s disease to identify genes that influence the amount of amyloid that accumulates in the brain. They found three genes that protected mice from brain amyloid accumulation and deposition. For each gene, lower expression in the liver protected the mouse brain. One of the genes encodes presenilinâ€”a cell membrane protein believed to contribute to the development of human Alzheimer’s.
“This unexpected finding holds promise for the development of new therapies to fight Alzheimer’s,” said Scripps Research Professor Greg Sutcliffe, who led the study. “This could greatly simplify the challenge of developing therapies and prevention.”
An estimated 5.1 million Americans have Alzheimer’s disease, including nearly half of people age 85 and older. By 2050, the number of people age 65 and over with this disease will range from 11 million to 16 million unless science finds a way to prevent or effectively treat it. In addition to the human misery caused by the disease, there is the unfathomable cost. A new report from the Alzheimer’s Association shows that in the absence of disease-modifying treatments, the cumulative costs of care for people with Alzheimer’s from 2010 to 2050 will exceed $20 trillion.
A Genetic Search-and-Find Mission
In trying to help solve the Alzheimer’s puzzle, in the past few years Sutcliffe and his collaborators have focused their research on naturally occurring, inherited differences in neurological disease susceptibility among different mouse strains, creating extensive databases cataloging gene activity in different tissues, as measured by mRNA accumulation. These data offer up maps of trait expression that can be superimposed on maps of disease modifier genes.
As is the case with nearly all scientific discovery, Sutcliffe’s research builds on previous findings. Several years ago, researchers at Case Western Reserve mapped three genes that modify the accumulation of pathological beta amyloid in the brains of a transgenic mouse model of Alzheimer’s disease to large chromosomal regions, each containing hundreds of genes. The Case Western scientists used crosses between the B6 and D2 strains of mice, studying more than 500 progeny.
Using the results from this study, Sutcliffe turned his databases of gene expression to the mouse model of Alzheimer’s, looking for differences in gene expression that correlated with differences in disease susceptibility between the B6 and D2 strains. This intensive work involved writing computer programs that identified each genetic difference that distinguished the B6 and D2 genomes, then running mathematical correlation analysis (known as regression analysis) of each difference. Correlations were made between the genotype differences (B6 or D2) and the amount of mRNA product made from each of the more than 25,000 genes in a particular tissue in the 40 recombinant inbred mouse strains. These correlations were repeated 10 times to cover 10 tissues, the liver being one of them.
“A key aspect of this work was learning how to ask questions of massive data sets to glean information about the identities of heritable modifier genes,” Sutcliffe said. “This was novel and, in a sense, groundbreaking work: we were inventing a new way to identify modifier genes, putting all of these steps together and automating the process. We realized we could learn about how a transgene’s pathogenic effect was being modified without studying the transgenic mice ourselves.”
Looking for a Few Good Candidates
Sutcliffe’s gene hunt offered up good matches, candidates, for each of the three disease modifier genes discovered by the Case Western scientists, and one of these candidatesâ€”the mouse gene corresponding to a gene known to predispose humans carrying particular variations of it to develop early-onset Alzheimer’s diseaseâ€”was of special interest to his team.
“The product of that gene, called Presenilin2, is part of an enzyme complex involved in the generation of pathogenic beta amyloid,” Sutcliffe explained. “Unexpectedly, heritable expression of Presenilin2 was found in the liver but not in the brain. Higher expression of Presenilin2 in the liver correlated with greater accumulation of beta amyloid in the brain and development of Alzheimer’s-like pathology.”
This finding suggested that significant concentrations of beta amyloid might originate in the liver, circulate in the blood, and enter the brain. If true, blocking production of beta amyloid in the liver should protect the brain.
To test this hypothesis, Sutcliffe’s team set up an in vivo experiment using wild-type mice since they would most closely replicate the natural beta amyloid-producing environment. “We reasoned that if brain amyloid was being born in the liver and transported to the brain by the blood, then that should be the case in all mice,” Sutcliffe said, “and one would predict in humans, too.”
The mice were administered imatinib (trade name Gleevec, an FDA-approved cancer drug), a relatively new drug currently approved for treatment of chronic myelogenous leukemia and gastrointestinal tumors. The drug imatinib (trade name Gleevec potently reduces the production of beta amyloid in neuroblastoma cells transfected by amyloid precursor protein (APP) and also in cell-free extracts prepared from the transfected cells. Importantly, Gleevec has poor penetration of the blood-brain barrier in both mice and humans.
“This characteristic of the drug is precisely why we chose to use it,” Sutcliffe explained. “Because it doesn’t penetrate the blood-brain barrier, we were able to focus on the production of amyloid outside of the brain and how that production might contribute to amyloid that accumulates in the brain, where it is associated with disease.”
The mice were injected with Gleevec twice a day for seven days; then plasma and brain tissue were collected, and the amount of beta amyloid in the blood and brain was measured. The findings: the drug dramatically reduced beta amyloid not only in the blood, but also in the brain where the drug cannot penetrate. Thus, an appreciable portion of brain amyloid must originate outside of the brain, and imatinib represents a candidate for preventing and treating Alzheimer’s.
As for the future of this research, Sutcliffe says he hopes to find a partner and investors to move the work into clinical trials and new drug development.
In addition to Sutcliffe, the authors of the study, titled “Peripheral reduction of Î²-amyloid is sufficient to reduce brain AÎ²: implications for Alzheimer’s disease,” include Peter Hedlund and Elizabeth Thomas of Scripps Research, and Floyd Bloom and Brian Hilbush of ModGene, LLC, which funded the project. For more information, see http://onlinelibrary.wiley.com/doi/10.1002/jnr.22603/abstract .
About The Scripps Research Institute
The Scripps Research Institute is one of the world’s largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute’s graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation. For more information, see http://www.scripps.edu .
ModGene is a preclinical research company specializing in mouse modifier genetics. Its core technology makes correlations between naturally occurring, heritable differences in disease susceptibility among different strains of mice and naturally occurring, heritable differences in the activities of the genes of these mice. This allows the company to gain insights into which proteins represent targets for the development of drugs that modify disease susceptibility. For more information, email firstname.lastname@example.org.
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Systematic (IUPAC) name
589.7 g/mol (mesilate)
eMolecules & PubChem
Hepatic (mainly CYP3A4-mediated)
18 hours (imatinib)
40 hours (active metabolite)
Fecal (68%) and renal (13%)
EMA:Link, US FDA:link
POM (UK) â„ž-only (US)
N(what is this?) (verify)
Imatinib (originally STI571) is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia/Latin America) as its mesylate salt, imatinib mesilate (INN). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and some other diseases. By 2011, Gleevec has been FDA approved to treat ten different cancers. In CML, the tyrosine kinase enzyme ABL is stuck in its activated form; imatinib binds to the site of tyrosine kinase activity, and prevents its activity.
Imatinib is the first member of a new class of agents that act by specifically inhibiting a certain enzyme that is characteristic of a particular cancer cell, rather than non-specifically inhibiting and killing all rapidly dividing cells, and served as a model for other targeted therapy modalities through tyrosine kinase inhibition.
â€¢ 1 History
â€¢ 2 Uses
o 2.1 Clinical
o 2.2 Experimental
â€¢ 3 Adverse effects
â€¢ 4 Pharmacology
o 4.1 Pharmacokinetics
o 4.2 Mechanism of action
â€¢ 5 Interactions
â€¢ 6 Costs
o 6.1 Legal challenge to generics
â€¢ 7 See also
â€¢ 8 References
â€¢ 9 External links
Imatinib was developed in the late 1990s by biochemist Nicholas Lydon, a former researcher for Novartis, and oncologist Brian Druker of Oregon Health and Science University (OHSU). Other major contributions to imatinib development were made by Carlo Gambacorti-Passerini, a physician scientist at University of Milano Bicocca, Italy, John Goldman at Hammersmith Hospital in London, UK, and later on by Charles Sawyers of Memorial Sloan-Kettering Cancer Center, who led the clinical trials confirming its efficacy in CML.
Imatinib was developed by rational drug design. After the Philadelphia chromosome mutation and hyperactive bcr-abl protein were discovered, the investigators screened chemical libraries to find a drug that would inhibit that protein. With high-throughput screening, they identified 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib.
Gleevec received FDA approval in May 2001. On the same month it made the cover of TIME magazine as the “magic bullet” to cure cancer. Druker, Lydon and Sawyers received the Lasker-DeBakey Clinical Medical Research Award in 2009 for “converting a fatal cancer into a manageable chronic condition”.
Imatinib is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-Kit. Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis. Early clinical trials also show its potential for treatment of hypereosinophilic syndrome and dermatofibrosarcoma protuberans.
In the United States, the Food and Drug Administration has approved imatinib as first-line treatment for CML. Imatinib has been shown to be more effective than the previous standard treatment of Î±-interferon and cytarabine.
Imatinib may also have a role in the treatment of pulmonary hypertension. It has been shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes, including portopulmonary hypertension.  In systemic sclerosis, the drug has been tested for potential use in slowing down pulmonary fibrosis. In laboratory settings, imatinib is being used as an experimental agent to suppress platelet-derived growth factor (PDGF) by inhibiting its receptor (PDGF-RÎ²). One of its effects is delaying atherosclerosis in mice without or with diabetes.
Recent mouse animal studies at Emory University in Atlanta have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur.
In vitro studies identified that a modified version of imatinib can bind to gamma-secretase activating protein (GSAP), which selectively increases the production and accumulation of neurotoxic beta-amyloid plaques. This suggests molecules that target at GSAP and are able to cross blood-brain barrier are potential therapeutic agents for treating Alzheimer’s disease. 
 Adverse effects
bcr-abl kinase (green), which causes CML, inhibited by imatinib (red; small molecule).
The most common side effects include weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), headache, edema, nausea, rash, and musculoskeletal pain.
Severe congestive cardiac failure is an uncommon but recognized side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium.
Imatinib is rapidly absorbed when given by mouth, and is highly bioavailable: 98% of an oral dose reaches the bloodstream. Metabolism of imatinib occurs in the liver and is mediated by several isozymes of the cytochrome P450 system, including CYP3A4 and, to a lesser extent, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. The main metabolite, N-demethylated piperazine derivative, is also active. The major route of elimination is in the bile and feces; only a small portion of the drug is excreted in the urine. Most of imatinib is eliminated as metabolites, only 25% is eliminated unchanged. The half-lives of imatinib and its main metabolite are 18 and 40 hours, respectively. It blocks the activity of Abelson cytoplasmic tyrosine kinase (ABL), c-Kit and the platelet-derived growth factor receptor (PDGFR). As an inhibitor of PDGFR, imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases. Imatinib has been reported to be an effective treatment for FIP1L1-PDGFRalpha+ mast cell disease, hypereosinophilic syndrome, and dermatofibrosarcoma protuberans.
 Mechanism of action
Imatinib is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.
There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor).
In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.
The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively. This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.
Imatinib is quite selective for bcr-abl â€“ it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known tyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl. Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions.
Since imatinib is mainly metabolised via the liver enzyme CYP3A4, substances influencing the activity of this enzyme change the plasma concentration of the drug. An example of a drug that increases imatinib activity and therefore side-effects by blocking CYP3A4 is ketoconazole. The same could be true of itraconazole, clarithromycin, grapefruit juice, among others. Conversely, CYP3A4 inductors like rifampicin and St. John’s Wort reduce the drug’s activity, risking therapy failure. Imatinib also acts as an inhibitor of CYP3A4, 2C9 and 2D6, increasing the plasma concentrations of a number of other drugs like simvastatin, ciclosporin, pimozide, warfarin, metoprolol, and possibly paracetamol. The drug also reduces plasma levels of levothyroxin via an unknown mechanism.
As with other immunosuppressants, application of live vaccines is contraindicated because the microorganisms in the vaccine could multiply and infect the patient. Inactivated and toxoid vaccines do not hold this risk, but may not be effective under imatinib therapy.
A box of 400-milligram Glivec tablets, as sold in Germany
The cost of Gleevec for CML is $32,000 to $98,000 a year, and for GIST is $64,800 a year.
Prices for a 100 mg pill of Gleevec internationally range from $20 to $30, although generic imatinib is cheaper.
 Legal challenge to generics
In 2007, imatinib became a test case through which Novartis challenged India’s patent laws. A win for Novartis would make it harder for Indian companies to produce generic versions of drugs still manufactured under patent elsewhere in the world. MÃ©decins Sans FrontiÃ¨res argues that a change in law would make it impossible for Indian companies to produce cheap generic antiretrovirals (anti-HIV medication), thus making it impossible for Third World countries to buy these essential medicines. On 6 August 2007 the Madras High Court dismissed the writ petition filed by Novartis challenging the constitutionality of Section 3(d) of Indian Patent Act and deferred to the World Trade Organization (WTO) forum to resolve the TRIPS compliance question. As of 2008 the case is unresolved.
 See also
â€¢ History of cancer chemotherapy
â€¢ Discovery and development of Bcr-Abl tyrosine kinase inhibitors
1. ^ a b A Conversation With Brian J. Druker, M.D., Researcher Behind the Drug Gleevec by Claudia Dreifus, The New York Times, November 2, 2009
2. ^ Gambacorti-Passerini C (2008). “Part I: Milestones in personalised medicine–imatinib”. Lancet Oncology 9 (600): 600. doi:10.1016/S1470-2045(08)70152-9. PMID 18510992.
3. ^ Druker BJ, Lydon NB (January 2000). “Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia”. J. Clin. Invest. 105 (1): 3â€“7. doi:10.1172/JCI9083. PMID 10619854. PMC 382593. http://www.jci.org/cgi/content/full/105/1/3.
4. ^ Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL (July 2006). “Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial”. Cancer 107 (2): 345â€“51. doi:10.1002/cncr.21996. PMID 16779792.
5. ^ a b Deininger MW, Druker BJ (September 2003). “Specific targeted therapy of chronic myelogenous leukemia with imatinib”. Pharmacol. Rev. 55 (3): 401â€“23. doi:10.1124/pr.55.3.4. PMID 12869662.
6. ^ Tapper EB, Knowles D, Heffron T, Lawrence EC, Csete M (June 2009). “Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition”. Transplant. Proc. 41 (5): 1969â€“71. doi:10.1016/j.transproceed.2009.02.100. PMID 19545770.
7. ^ Boucher P, Gotthardt M, Li WP, Anderson RG, Herz J (April 2003). “LRP: role in vascular wall integrity and protection from atherosclerosis”. Science 300 (5617): 329â€“32. doi:10.1126/science.1082095. PMID 12690199.
8. ^ Lassila M, Allen TJ, Cao Z, et al. (May 2004). “Imatinib attenuates diabetes-associated atherosclerosis”. Arterioscler. Thromb. Vasc. Biol. 24 (5): 935â€“42. doi:10.1161/01.ATV.0000124105.39900.db. PMID 14988091.
9. ^ Reeves PM, Bommarius B, Lebeis S, et al. (July 2005). “Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases”. Nat. Med. 11 (7): 731â€“9. doi:10.1038/nm1265. PMID 15980865.
10. ^ He G, Luo W, Li P, et al. (September 2010). “Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease”. Nature 467 (7311): 95â€“8. doi:10.1038/nature09325. PMID 20811458.
11. ^ a b Haberfeld, H, ed (2009) (in German). Austria-Codex (2009/2010 ed.). Vienna: Ã–sterreichischer Apothekerverlag. ISBN 3-85200-196-X.
12. ^ KerkelÃ¤ R, Grazette L, Yacobi R, et al. (August 2006). “Cardiotoxicity of the cancer therapeutic agent imatinib mesylate”. Nat. Med. 12 (8): 908â€“16. doi:10.1038/nm1446. PMID 16862153.
13. ^ Scheinfeld N, Schienfeld N (February 2006). “A comprehensive review of imatinib mesylate (Gleevec) for dermatological diseases”. J Drugs Dermatol 5 (2): 117â€“22. PMID 16485879.
14. ^ Takimoto CH, Calvo E. “Principles of Oncologic Pharmacotherapy” in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
15. ^ Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L (February 2003). “Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias”. Lancet Oncol. 4 (2): 75â€“85. doi:10.1016/S1470-2045(03)00979-3. PMID 12573349.
16. ^ Vigneri P, Wang JY (February 2001). “Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase”. Nat. Med. 7 (2): 228â€“34. doi:10.1038/84683. PMID 11175855.
17. ^ Klopp, T, ed (2010) (in German). Arzneimittel-Interaktionen (2010/2011 ed.). Arbeitsgemeinschaft fÃ¼r Pharmazeutische Information. ISBN 978-3-85200-207-1.
18. ^ Schiffer CA (July 2007). “BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia”. N. Engl. J. Med. 357 (3): 258â€“65. doi:10.1056/NEJMct071828. PMID 17634461.
19. ^ As Pills Treat Cancer, Insurance Lags Behind, By ANDREW POLLACK, New York Times, April 14, 2009
20. ^ Living With a Formerly fatal Blood Cancer, By JANE E. BRODY, New York Times, January 18, 2010
21. ^ Kelley RK, Venook AP (August 2010). “Nonadherence to imatinib during an economic downturn”. N. Engl. J. Med. 363 (6): 596â€“8. doi:10.1056/NEJMc1004656. PMID 20818898.
22. ^ Patented Medicine Review Board (Canada). Report on New Patented Drugs – Gleevec.
23. ^ pharmacychecker.com
24. ^ MÃ©decins Sans FrontiÃ¨res. “As Novartis Challenges India’s Patent Law, MSF Warns Access to Medicines Is Under Threat”, 2006-09-26. Accessed 2006-02-10.
 External links
â€¢ NCI Drug Information Summary for Patients
[show]v â€¢ d â€¢ eTargeted therapy / extracellular chemotherapeutic agents/antineoplastic agents (L01)
Receptor tyrosine kinase
ErbB: HER1/EGFR (Cetuximab, Panitumumab) â€¢ HER2/neu (Trastuzumab)
Others for solid tumors EpCAM (Catumaxomab, Edrecolomab) â€¢ VEGF-A (Bevacizumab)
lymphoid: CD20 (Ibritumomab, Ofatumumab, Rituximab, Tositumomab), CD52 (Alemtuzumab)
myeloid: CD33 (Gemtuzumab)
Receptor tyrosine kinase
ErbB: HER1/EGFR (Erlotinib, Gefitinib, Vandetanib) â€¢ HER1/EGFR and HER2/neu (Afatinib, Lapatinib, Neratinib)
RTK class III: C-kit and PDGFR (Axitinib, Pazopanib, Sunitinib, Sorafenib, Toceranib) â€¢ FLT3 (Lestaurtinib)
VEGFR (Axitinib, Cediranib, Pazopanib, Regorafenib, Semaxanib, Sorafenib, Sunitinib, Toceranib, Vandetanib)
bcr-abl (Dasatinib, Imatinib, Nilotinib)
Janus kinase 2 (Lestaurtinib)
tumr, epon, para
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