Previously I have written about the roles of glia and microglia in Alzheimer’s disease and in spinal cord injury. This blog entry reports on recent research which documents the importance of glial pathology as a general underlying factor in essentially all age related neurodegenerative diseases including Alzheimer’s Disease, Parkinson’s Disease, advanced spinal degeneration, ALS, multiple sclerosis, and several retinal diseases.
“Glial cells,, sometimes called neuroglia or simply glia (Greek γλία, γλοία “glue”; pronounced in English either /gliːə/ or /glaɪə/), are non-neuronalcells that maintain homeostasis, form myelin, and provide support and protection for the brain’s neurons. In the human brain, there is roughly one glia for every neuron with a ratio of about two neurons for every glia in the cerebral gray matter. — As the Greek name implies, glia are commonly known as the glue of the nervous system; however, this is not fully accurate. Neuroscience currently identifies four main functions of glial cells: to surround neurons and hold them in place, to supply nutrients and oxygen to neurons, to insulate one neuron from another, and to destroy pathogens and remove dead neurons. For over a century, it was believed that they did not play any role in neurotransmission. That idea is now discredited; they do modulate neurotransmission, although the mechanisms are not yet well understood(ref).” In addition, as we will see, glia play several key roles required for maintenance of nervous system health.
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system (CNS). Microglia constitute 20% of the total glial cell population within the brain. Microglia (and astrocytes, another type of glial cells) are distributed in large non-overlapping regions throughout the brain and spinal cord. Microglia are constantly scavenging the CNS for damaged neurons, plaques, and infectious agents. The brain and spinal cord are considered “immune privileged” organs in that they are separated from the rest of the body by a series of endothelial cells known as the blood-brain barrier, which prevents most infections from reaching the vulnerable nervous tissue. In the case where infectious agents are directly introduced to the brain or cross the blood-brain barrier, microglial cells must react quickly to decrease inflammation and destroy the infectious agents before they damage the sensitive neural tissue. Due to the unavailability of antibodies from the rest of the body (few antibodies are small enough to cross the blood brain barrier), microglia must be able to recognize foreign bodies, swallow them, and act as antigen-presenting cells activating T-cells. Since this process must be done quickly to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS(ref).”
Background: earlier blog entries
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. In the March 2011 blog entry Alzheimer’s Disease Update I included a discussion on this hypothesis and on how with aging microglia lose their capability to get rid of beta amyloid via phagocytosis. That same blog entry also cites publications arguing that, to a considerable extent, aging-related neurodegenerative diseases appear to depend on the same underlying mechanisms. I mention microglial activation in a number of additional blog entries. In particular, I discuss the role of microglial activation in spinal cord injuries and in the generation of neuropathic pain in the blog entry Spinal cord injury pain.
While I have previously cited a number of publications relevant to the theme of the current blog entry, I restrict myself here to reviewing publications I have not discussed before.
There is wide agreement that excessive microglial activation is a key process in nervous system disorders involving release of strong pro-inflammatory cytokines, cytokines which can trigger worsening of multiple disease states.
Microglial activation can involve a variety of responses to injury, disease or insult. It is not a single process as pointed out in the 2005 article The microglial “activation” continuum: from innate to adaptive responses. “While classically regarded as macrophage-like cells, it is becoming increasingly clear that reactive microglia play more diverse roles in the CNS. Microglial “activation” is often used to refer to a single phenotype; however, in this review we consider that a continuum of microglial activation exists, with phagocytic response (innate activation) at one end and antigen presenting cell function (adaptive activation) at the other. Where activated microglia fall in this spectrum seems to be highly dependent on the type of stimulation provided. We begin by addressing the classical roles of peripheral innate immune cells including macrophages and dendritic cells, which seem to define the edges of this continuum. We then discuss various types of microglial stimulation, including Toll-like receptor engagement by pathogen-associated molecular patterns, microglial challenge with myelin epitopes or Alzheimer’s β-amyloid in the presence or absence of CD40L co-stimulation, and Alzheimer disease “immunotherapy”. Based on the wide spectrum of stimulus-specific microglial responses, we interpret these cells as immune cells that demonstrate remarkable plasticity following activation. This interpretation has relevance for neurodegenerative/neuroinflammatory diseases where reactive microglia play an etiological role; in particular viral/bacterial encephalitis, multiple sclerosis and Alzheimer disease.”
The October 2011 publication Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases reports “Microglia are activated in response to a number of different pathological states within the CNS including injury, ischemia, and infection. Microglial activation results in their production of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α. While release of these factors is typically intended to prevent further damage to the CNS tissue, they may also be toxic to neurons and other glial cells. Mounting evidence indicates that chronic microglial activation may also contribute to the development and progression neurodegenerative disorders. Unfortunately, determining the role of pro-inflammatory cytokines in these disorders has been complicated by their dual roles in neuroprotection and neurodegeneration. The purpose of this review is to summarize current understanding of the involvement of cytokines in neurodegenerative disorders and their potential signaling mechanisms in this context. Taken together, recent findings suggest that microglial activation and pro-inflammatory cytokines merit interest as targets in the treatment of neurodegenerative disorders.”
As is often the case in disease processes, when it comes to microglial activation cause and effect can be confounded. Activated microglia and activated astrocytes surrounding amyloid plaques can increase the plaque deposits of beta amyloid in the case of AD just as the presence of beta amyloid plaque deposits leads to activated microglia and astrocytes. There appears to be a positive feedback loop between these processes in the case of AD and I do not think it is clear at this point that one of these processes is primary to the others.
Aging is a key factor leading microglia to be more prone to aberrant activation.
This point has been made frequently and for a long time in the literature. It can be found, for example, in the 1999 publication Increased microglial activation and protein nitration in white matter of the aging monkeyand in the October 2011 publicationLipopolysaccharide-induced interleukin (IL)-4 receptor-α expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice.
In Alzheimer’s Disease, microglia activated by beta amyloid could contribute to the pathology by inhibiting intercellular communication mediated by gap junctions.
This conjecture has also been known for some time. The 2006 publication Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: potentiation by beta-amyloid reported “Brain inflammation is characterized by a reactive gliosis involving the activation of astrocytes and microglia. This process, common to many brain injuries and diseases, underlies important phenotypic changes in these two glial cell types. One characteristic feature of astrocytes is their high level of intercellular communication mediated by gap junctions. Previously, we have reported that astrocyte gap junctional communication (AGJC) and the expression of connexin 43 (Cx43), the main constitutive protein of gap junctions, are inhibited in microglia (MG)-astrocyte cocultures. Here, we report that bacterial lipopolysaccharide activation of microglia increases their inhibitory effect on Cx43 expression and AGJC. This inhibition is mimicked by treating astrocyte cultures with conditioned medium harvested from activated microglia. Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were identified as being the main factors responsible for this conditioned medium-mediated activity. Interestingly, an inflammatory response characterized by MG activation and reactive astrocytes occurs in Alzheimer’sdisease, at sites of beta-amyloid (Abeta) deposits. We found that this peptide potentiates the inhibitory effect of a conditioned medium diluted at a concentration that is not effective per se. This potentiation is prevented by treating astrocytes with specific blockers of IL-1beta and TNF-alpha activities. Thus, the suppression of communication between astrocytes, induced by activated MG could contribute to the proposed role of reactive gliosis in this neurodegenerative disease.”
In Alzheimers’s disease,neurons are killed by a cascade of hemichannel activation triggered by beta amyloid leading to activated microglia releasing glutamate and ATP through glial (microglia and astrocytes) hemichannels.
The March 2011 publication Amyloid β-induced death in neurons involves glial and neuronal hemichannelsreports: “The mechanisms involved in Alzheimer’sdisease are not completely understood and how glial cells contribute to this neurodegenerative disease remains to be elucidated. Because inflammatory treatments and products released from activated microglia increase glial hemichannel activity, we investigated whether amyloid-β peptide (Aβ) could regulate these channels in glial cells and affect neuronal viability. Microglia, astrocytes, or neuronal cultures as well as acute hippocampal slices made from GFAP-eGFP transgenic mice were treated with the active fragment of Aβ. Hemichannel activity was monitored by single-channel recordings and by time-lapse ethidium uptake, whereas neuronal death was assessed by Fluoro-Jade C staining. We report that low concentrations of Aβ(25-35) increased hemichannel activity in all three cell types and microglia initiate these effects triggered by Aβ. Finally, neuronal damage occurs by activation of neuronal hemichannels induced by ATP and glutamate released from Aβ(25-35)-activated glia. These responses were observed in the presence of external calcium and were differently inhibited by hemichannel blockers, whereas the Aβ(25-35)-induced neuronal damage was importantly reduced in acute slices made from Cx43 knock-out mice. Thus, Aβ leads to a cascade of hemichannel activation in which microglia promote the release of glutamate and ATP through glial (microglia and astrocytes) hemichannels that induces neuronal death by triggering hemichannels in neurons. Consequently, this work opens novel avenues for alternative treatments that target glial cells and neurons to maintain neuronal survival in the presence of Aβ.”
“ — Brains from AD patients exhibit a reactive gliosis characterized by glial activation closely associated with amyloid plaques (Kalaria, 1999). Moreover, it has been reported that the immunoreactivity of connexin 43 (Cx43), a gap junction channel and hemichannel protein subunit (Sáez et al., 2003), is increased around amyloid plaques (Nagy et al., 1996; Mei et al., 2010). Gap junctions are membrane specializations that provide a direct cytoplasmic pathway between contacting cells by aggregates that contain a few tens to thousands of cell-to-cell channels, termed gap junction channels (Sáez et al., 2003). They are formed by the docking of two hemichannels, contributed by each contacting cell (Sáez et al., 2003). Each hemichannel is formed by oligomerization of connexins, which are expressed by astrocytes, microglia, and neurons (Orellana et al., 2009). A more recently described three-member protein family, termed pannexins (Panxs), can also form hemichannels at the cell surface of diverse mammalian cells (Scemes et al., 2009) and have been proposed to play a relevant role in inflammasome activation in astrocytes and neurons (Iglesias et al., 2009). — It has been proposed that, under chronic pathological conditions (e.g., AD), activated microglia release proinflammatory molecules that increase hemichannel opening and reduce gap junctional communication in astrocytes, depriving neurons of glial protective functions and further reducing neuronal viability (Orellana et al., 2009). In fact, increased hemichannel activity occurs in astrocytes, microglia, and neurons under in vitro conditions that mimic pathological situations (Takeuchi et al., 2006; Thompson et al., 2006; Orellana et al., 2010)(ref).”
Ion channels on microglia play key roles in microglial activation.
The 2011 publicationReview Ion channels on microglia: therapeutic targets for neuroprotectionreports:“Under pathological conditions microglia (resident CNS immune cells) become activated, and produce reactive oxygen and nitrogen species and pro-inflammatory cytokines: molecules that can contribute to axon demyelination and neuron death. Because some microglia functions can exacerbate CNS disorders, including stroke, traumatic brain injury, progressive neurodegenerative disorders such as Alzheimer’sdisease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, and several retinal diseases, controlling their activation might ameliorate immune-mediated CNS disorders. A growing body of evidence now points to ion channels on microglia as contributing to the above neuropathologies. For example, the ATP-gated P2X7 purinergic receptor cation channel is up-regulated around amyloid β-peptide plaques in transgenic mouse models of Alzheimer’sdisease and co-localizes to microglia and astrocytes. Upregulation of the P2X7 receptor subtype on microglia occurs also following spinal cord injury and after ischemia in the cerebral cortex of rats, while P2X7 receptor-like immunoreactivity is increased in activated microglial cells of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. Utilizing neuron/microglia co-cultures as an in vitro model for neuroinflammation, P2X7 receptor activation on microglia appears necessary for microglial cell-mediated injury of neurons. A second example can be found in the chloride intracellular channel 1 (CLIC1), whose expression is related to macrophage activation, undergoes translocation from the cytosol to the plasma membrane (activation) of microglia exposed to amyloid β-peptide, and participates in amyloid β-peptide-induced neurotoxicity through the generation of reactive oxygen species. A final example is the small-conductance Ca2+/calmodulin-activated K+ channel KCNN4/KCa3.1/SK4/IK1, which is highly expressed in rat microglia. Lipopolysaccharide-activated microglia are capable of killing adjacent neurons in co-culture, and show markedly reduced toxicity when treated with an inhibitor of KCa3.1 channels. Moreover, blocking KCa3.1 channels mitigated the neurotoxicity of amyloid β-peptide-stimulated microglia. Excessive microglial cell activation and production of potentially neurotoxic molecules, mediated by ion channels, may thus constitute viable targets for the discovery and development of neurodegenerative disease therapeutics”.
A December 2011 publication Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia reports on the roles of ion channels in microglia in Alzheimer’s Disease. “Production of reactive oxygen species (ROS) by microglial cells and subsequent oxidative stress are strongly implicated in the pathogenesis of Alzheimer’s disease. Although it is recognized that amyloid-β (Aβ) plays a major role in inducing and regulating microglial ROS production in Alzheimer’s disease, to date little is known about cellular mechanisms underlying Aβ-stimulated ROS production. Here, we identified ion channels involved in Aβ-induced microglial ROS production and in Aβ-induced microglial priming. Acute stimulation of microglial cells with either fibrillar Aβ(1-42) (fAβ(1-42) ) or soluble Aβ(1-42) (sAβ(1-42) ) caused significant increases in microglial ROS production, which were abolished by inhibition of TRPV1 cation channels with 5-iodo-resiniferatoxin (I-RTX), but were unaffected by inhibition of K(+) channels with charybdotoxin (CTX). Furthermore, pretreatment with either fAβ(1-42) or sAβ(1-42) induced microglial priming, that is, increased ROS production upon secondary stimulation with the phorbol ester PMA. Microglial priming induced by fAβ(1-42) or sAβ(1-42) remained unaffected by TRPV1 channel inhibition with I-RTX. However, sAβ(1-42) -induced priming was inhibited by CTX and margatoxin, but not by TRAM-34 or paxilline, indicating a role of Kv1.3 voltage-gated K(+) channels, but not of Ca(2+) -activated K(+) channels, in the priming process. In summary, our data suggest that in microglia Aβ-induced ROS production and priming are differentially regulated by ion channels, and that TRPV1 cation channels and Kv1.3 K(+) channels may provide potential therapeutic targets to reduce microglia-induced oxidative stress in Alzheimer’s disease.”
The October 2011 publication Glial connexin expression and function in the context of Alzheimer’s disease reports: “A hallmark of neurodegenerative diseases is the reactive gliosis characterized by a phenotypic change in astrocytes and microglia. This glial response is associated with modifications in the expression and function of connexins (Cxs), the proteins forming gap junction channels and hemichannels. Increased Cx expression is detected in most reactive astrocytes located at amyloid plaques, the histopathological lesions typically present in the brain of Alzheimer’s patients and animal models of the disease. The activity of Cx channels analyzed in vivo as well as in vitro after treatment with the amyloid β peptide is also modified and, in particular, hemichannel activation may contribute to neuronal damage. In this review, we summarize and discuss recent data that suggest glial Cx channels participate in the neurodegenerative process of Alzheimer’s disease.”
Yet-another publication related to connexins is the December 2010 document Astroglial connexin immunoreactivity is specifically altered at β-amyloid plaques in β-amyloid precursor protein/presenilin1 mice.
Glia are seen as very important for the understanding of and development of treatments for Parkinson’s Disease.
The 2008 publication Glial reactions in Parkinson’s disease raised the issue of whether glial activation is an important component in the etiology of Parkinson’s disease (PD). “Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the presence of tremor, muscle rigidity, slowness of voluntary movements and postural instability. One of the pathological hallmarks of PD is loss of dopaminergic (DAergic) neurons in the subtantia nigra pars compacta (SNpc). The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are not fully understood, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD, but whether astroglia activation may protect or exacerbate DAergic neuron loss is the subject of much debate. Astrocytes and microglia are the key players in neuroinflammatory responses, secreting an array of pro- and anti-inflammatory cytokines, anti-oxidants and neurotrophic factors. These mediators act as double-edged swords, exerting both detrimental and neuroprotective effects. Here, the contribution of astrocytes and microglia in mediating the effects of both genetic and environmental factors, including hormones, endotoxins and neurotoxins, and their ability to influence DAergic neurodegeneration, neuroprotection and neurorepair will be discussed. Approaches capable to regulate glial-associated oxidative stress and mitochondrial damage, by decreasing inflammatory burden, restoring mitochondrial function and DAergic neuron metabolism, might hold great promise for therapeutic interventions. Therapies that support astrocyte function, replacing astrocytes either modified or unmodified in culture, may represent novel approaches targeting astrocytes to promote DAergic neurorescue. Dissecting the molecular determinants of glia-neuron crosstalk will give us the possibility to test novel strategies to promote restoration of injured nigrostriatal DAergic neurons.”
The 2010 publicationGlia as a turning point in the therapeutic strategy of Parkinson’s diseasefurtherarticulated this issue. “Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the presence of tremor, muscle rigidity, slowness of voluntary movements and postural instability. One of the pathological hallmarks of PD is loss of dopaminergic (DAergic) neurons in the subtantia nigra pars compacta (SNpc). The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are not fully understood, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD, but whether astroglia activation may protect or exacerbate DAergic neuron loss is the subject of much debate. Astrocytes and microglia are the key players in neuroinflammatory responses, secreting an array of pro- and anti-inflammatory cytokines, anti-oxidants and neurotrophic factors. These mediators act as double-edged swords, exerting both detrimental and neuroprotective effects. Here, the contribution of astrocytes and microglia in mediating the effects of both genetic and environmental factors, including hormones, endotoxins and neurotoxins, and their ability to influence DAergic neurodegeneration, neuroprotection and neurorepair will be discussed. Approaches capable to regulate glial-associated oxidative stress and mitochondrial damage, by decreasing inflammatory burden, restoring mitochondrial function and DAergic neuron metabolism, might hold great promise for therapeutic interventions. Therapies that support astrocyte function, replacing astrocytes either modified or unmodified in culture, may represent novel approaches targeting astrocytes to promote DAergic neurorescue. Dissecting the molecular determinants of glia-neuron crosstalk will give us the possibility to test novel strategies to promote restoration of injured nigrostriatal DAergic neurons.”
While microglial activation and inflammatory signaling may increase markedly with advanced age, the result is not necessarily a significant decrease in cognitive performance or loss of memory.
The October 2011 publication Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment reports “Age-related cognitive dysfunction, including impairment of hippocampus-dependent spatial learning and memory, affects approximately half of the aged population. Induction of a variety of neuroinflammatory measures has been reported with brain aging but the relationship between neuroinflammation and cognitive decline with non-neurodegenerative, normative aging remains largely unexplored. This study sought to comprehensively investigate expression of the MHC II immune response pathway and glial activation in the hippocampus in the context of both aging and age-related cognitive decline. — We report a marked age-related induction of neuroinflammatory signaling transcripts (i.e., MHC II components, toll-like receptors, complement, and downstream signaling factors) throughout the hippocampus in all aged rats regardless of cognitive status. Astrocyte and microglialactivation was evident in CA1, CA3 and DG of intact and impaired aged rat groups, in the absence of differences in total numbers of GFAP+ astrocytes or Iba1+ microglia. Both mild and moderate microglialactivation was significantly increased in all three hippocampal subregions in aged cognitively intact and cognitively impaired rats compared to adults. Neither induction of MHCII pathway gene expression nor glial activation correlated to cognitive performance. — CONCLUSIONS: These data demonstrate a novel, coordinated age-related induction of the MHC II immune response pathway and glial activation in the hippocampus, indicating an allostatic shift toward a para-inflammatory phenotype with advancing age. Our findings demonstrate that age-related induction of these aspects of hippocampal neuroinflammation, while a potential contributing factor, is not sufficient by itself to elicit impairment of spatial learning and memory in models of normative aging. Future efforts are needed to understand how neuroinflammation may act synergistically with cognitive-decline specific alterations to cause cognitive impairment.”
Epigenetic state of the individual and programming from earlier events may determine how glia respond in the case of neurocognitive and inflammatory disorders.
The August 2011 publication A Lifespan Approach to Neuroinflammatory and Cognitive Disorders: A Critical Role for Gliareports: “Cognitive decline is a common problem of aging. Whereas multiple neural and glial mechanisms may account for these declines, microglial sensitization and/or dystrophy has emerged as a leading culprit in brain aging and dysfunction. However, glial activation is consistently observed in normal brain aging as well, independent of frank neuroinflammation or functional impairment. Such variability suggests the existence of additional vulnerability factors that can impact neuronal-glial interactions and thus overall brain and cognitive health. The goal of this review is to elucidate our working hypothesis that an individual’s risk or resilience to neuroinflammatory disorders and poor cognitive aging may critically depend on their early life experience, which can change immune reactivity within the brain for the remainder of the lifespan. For instance, early-life infection in rats can profoundly disrupt memory function in young adulthood, as well as accelerate age-related cognitive decline, both of which are linked to enduring changes in glial function that occur in response to the initial infection. — We discuss these findings within the context of the growing literature on the role of immune molecules and neuroimmune crosstalk in normal brain development. We highlight the intrinsic factors (e.g., chemokines, hormones) that regulate microglial development and their colonization of the embryonic and postnatal brain, and the capacity for disruption or “re-programming” of this crucial process by external events (e.g., stress, infection). An impact on glia, which in turn alters neural development, has the capacity to profoundly impact cognitive and mental health function at all stages of life.”
A stem cell therapy may be developed that acts on microglia so as to decrease beta amyloid plaques in the case of Alzheimer’s disease.
The October 2011 publication Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-β plaques, e-publication ahead of print, reports “Presently, co-culture of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) with BV2 microglia under amyloid-β42 (Aβ42) exposure induced a reduction of Aβ42 in the medium as well as an overexpression of the Aβ-degrading enzyme neprilysin (NEP) in microglia. Cytokine array examinations of co-cultured media revealed elevated release of soluble intracellular adhesion molecule-1 (sICAM-1) from hUCB-MSCs. Administration of human recombinant ICAM-1 in BV2 cells and wild-type mice brains induced NEP expression in time- and dose-dependent manners. In co-culturing with BV2 cells under Aβ42 exposure, knockdown of ICAM-1 expression on hUCB-MSCs by small interfering RNA (siRNA) abolished the induction of NEP in BV2 cells as well as reduction of added Aβ42 in the co-cultured media. By contrast, siRNA-mediated inhibition of the sICAM-1 receptor, lymphocyte function-associated antigen-1 (LFA-1), on BV2 cells reduced NEP expression by ICAM-1 exposure. When hUCB-MSCs were transplanted into the hippocampus of a 10-month-old transgenic mouse model of Alzheimer’s disease for 10, 20, or 40 days, NEP expression was increased in the mice brains. Moreover, Aβ42 plaques in the hippocampus and other regions were decreased by active migration of hUCB-MSCs toward Aβ deposits. These data suggest that hUCB-MSC-derived sICAM-1 decreases Aβ plaques by inducing NEP expression in microglia through the sICAM-1/LFA-1 signaling pathway.
It is not clear that enhancing NEP expression and clearing beta amyloid will clear up AD, however, since it may create other serious problems. At least that appears to be the case in fruit flys as reported in the 2008 publication Overexpression of neprilysin reduces alzheimer amyloid-beta42 (Abeta42)-induced neuron loss and intraneuronal Abeta42 deposits but causes a reduction in cAMP-responsive element-binding protein-mediated transcription, age-dependent axon pathology, and premature death in Drosophila.
Neuroinflammatory reactions in glia can be inhibited by various means. However, consequences of such inhibition on susceptibility to neuroinflammatory diseases or of prognosis of disease progress is not clear.
I suspect that a wide variety of anti-inflammatory substances which are inhibitors of “the usual suspect” inflammatory molecules like NF-kappaB, IL1-beta and TNF-alpha will work to a greater or lesser extent. One such substances is discussed in the October 2011 publication Inhibitory effect of a tyrosine-fructose Maillard reaction product, 2,4-bis(p-hydroxyphenyl)-2-butenal on amyloid-beta generation and inflammatory reactions via inhibition of NF- kappaB and STAT3 activation in cultured astrocytes and microglial BV-2 cells.
Aspirin is another such substance, as indicated in the August 2011 publication Aspirin-triggered lipoxin A4 attenuates LPS-induced pro-inflammatory responses by inhibiting activation of NF-κB and MAPKs in BV-2 microglial cells. “This study indicates that ATL inhibits NO and pro-inflammatory cytokine production at least in part via NF-κB, ERK, p38 MAPK and AP-1 signaling pathways in LPS-activated microglia. Therefore, ATL may have therapeutic potential for various neurodegenerative diseases.” Back in 1934, my primary care physician would probably have agreed with the last statement without knowing why.
“One way to control neuroinflammation is to inhibit microglial activation. Studies on microglia have shown that they are activated by diverse stimuli but they are dependent on activation of mitogen-activated protein kinase (MAPK). Previous approaches to down-regulate activated microglia focused on immunosuppressants. Recently, minocycline (a tetracycline derivative) has shown down-regulation of microglial MAPK. Another promising treatment is CPI-1189, which induces cell death in a TNF α-inhibiting compound that also down-regulates MAPK. Recent study shows that nicergoline (Sermion) suppresses the production of proinflammatory cytokines and superoxide anion by activated microglia(ref).”
As a matter of fact, certain foods as well as some of the thirty six substances in my anti-aging firewalls supplement regimen which inhibit expression of NF-kappaB s may be protective against neurodegenerative diseases by limiting microglial activation.
The 2010 publication Blueberry supplementation attenuates microglial activation in hippocampal intraocular grafts to aged hosts discusses one such food. “– we here report decreased microglial activation and astrogliosis in intraocular hippocampal grafts to middle-aged hosts fed a 2% blueberry diet. Markers for astrocytes and for activated microglial cells were both decreased long-term after grafting to blueberry-treated hosts compared with age-matched rats on a control diet. Similar findings were obtained in the host brain, with a reduction in OX-6 immunoreactive microglial cells in the hippocampus of those recipients treated with blueberry. In addition, immunoreactivity for the pro-inflammatory cytokine IL-6 was found to be significantly attenuated in intraocular grafts by the 2% blueberry diet. These studies demonstrate direct effects of blueberry upon microglial activation both during isolated conditions and in the aged host brain and suggest that this nutraceutical can attenuate age-induced inflammation.”
Other natural substances that can be protective against microglial activation are curcumin(ref)(ref), grape seed extract(ref), and oh yes, caffeine and coffee(ref)(ref). I expect we will be hearing more about the inhibition of microglial activation by various phyto-substances and the consequent possible prevention or treatment of age-related nervous system diseases as time progresses.
I wish there was a place to simply post links to interesting research Vince?
Anyhow; the following has some relivance to this topic as it activates P53 and is instrumental in DNA repair:
This is way off subject, but here are some more substances that may be worth looking into for DNA repair:
A quick search of your site and blog seem to indicate that there is little in the line of mineral research? This you may find interesting:
As always; thanks for the well written and researched posts and site Vince; insperational! 🙂
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