Alzheimer’s disease (AD) is a progressive and fatal disease affecting as many as 5.2 million Americans, the fourth most common cause of death in developing nations. There are various treatments for symptoms of AD but as of now there is no cure(ref). My purposes here are 1. to review a chain of research findings that seem to point to the cause of AD and how ultimately to prevent it, and 2. To review research and clinical trials that may in the more immediate future provide therapies that slow the destructive process of AD.
In case you have forgotten, “Alzheimer’s disease is a neurodegenerative disorder that represents the most important cause of dementia in humans. Extracellular deposits of Î²-amyloid peptides (AÎ²), often termed senile plaques, and formation of intracellular neurofibrillary tangles of hyperphosphorylated tau protein are the two principal hallmarks of this disease. AÎ² aggregates are known to induce synaptic dysfunction, and thus are linked with learning and memory deficits in both human and mouse models of the disease, making AÎ² deposits a target for prevention or treatment(ref).”
Microglia are intimately involved in the maintenance of normal brain functioning and in the etiology of many neurodegenerative conditions, including AD. “Microglia are a type of glial cells 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) are distributed in large non-overlapping regions throughout the brain and spinal cord. Microglia are constantly excavating the CNS for damaged neurons, plaques, and infectious agents(ref).”
One role of microglia, that of amplifying pain, was introduced in the blog post Spinal cord injury pain. There have been various theories as to the involvement of microglia in AD including a very interesting new one. Physically, “Microglia are attracted to AÎ² aggregates and decorate plaques. Such a phenomenon has been observed in both human and transgenic mouse model of Alzheimer’s disease, suggesting an important role for these cells in the CNS(ref).”
AD, microglia and cellular senescence
Over less than a decade there has been a 180 degree shift from seeing microglial activation as a main cause of AD to seeing microglial senescence as a main cause of AD.
For a period of time many researchers thought that microglial activation caused by AÎ² plaque creates an inflammatory condition that results in neuron degeneration in AD. The 2004 publication Microglia and neuroinflammation: a pathological perspective makes the point that this view is far too simplistic. “The idea that neuroinflammation is detrimental implies that glial cell activation precedes and causes neuronal degeneration , a sequence of events that appears to be at odds with experimental models of neurodegeneration in which glial cell activation occurs secondary to neuronal damage. What is missing from this simple linear model is the understanding that chronic neurological diseases are just that – chronic, and that this chronicity introduces complex interactions and feedback loops between neurons and glia that render attempts to construct simple, linear cascades of cause and effect inelegant.” However, this publication concludes “Chronic microglial activation is an important component of neurodegenerative diseases, and this chronic neuroinflammatory component likely contributes to neuronal dysfunction, injury, and loss (and hence to disease progression) in these diseases.”
The 2006 paper Microglial senescence: does the brain’s immune system have an expiration date? suggests that replicative senescence of microglia might have to do with neurodegenerative diseases like AD, a theme to be picked up more powerfully later.
By mid-2008 a much more positive role for microglia in AD was emerging as exemplified in the publication Debris clearance by microglia: an essential link between degeneration and regeneration“In Alzheimer disease microglia can be beneficial by phagocytosing AÎ² or harmful by secretion of neurotoxins. Recently it was shown in an animal model of Alzheimer disease plaque formation that microglia accumulation is associated with rapid appearance and local toxicity of AÎ² plaques — Thus, there is certain evidence that either local microglia or invading blood-derived macrophages restrict AÎ² deposits in an animal model of Alzheimer disease.” The same publication points out that microglia are subject to replicative cellular senescence implying age-related decline in their phagocytic activity. “Ageing is associated with senescence of microglia and impaired microglial clearance functions. In particular, data indicate that microglia in aged rodent and human brains show a replicative senescence with a reduced self-renewal capacity (Streit, 2006). Microglia in aged animals were characterized by the presence of lipofuscin granules, decreased processes complexity, altered granularity and increased mRNA expression of pro-inflammatory cytokines such as TNF-alpha and IL-1Î² (Sierra et al., 2007
Finally, the role of microglial senescence in AD was clearly delineated in the October 2009 publication Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease-“– the purpose of this study was to investigate microglial cells in situ and at high resolution in the immediate vicinity of tau-positive structures in order to determine conclusively whether degenerating neuronal structures are associated with activated or with dystrophic microglia. — We now report histopathological findings from 19 humans covering the spectrum from none to severe AD pathology, including patients with Down’s syndrome, showing that degenerating neuronal structures positive for tau (neuropil threads, neurofibrillary tangles, neuritic plaques) are invariably colocalized with severely dystrophic (fragmented) rather than with activated microglial cells. Using Braak staging of Alzheimer neuropathology we demonstrate that microglial dystrophy precedes the spread of tau pathology. Deposits of amyloid-beta protein (Abeta) devoid of tau-positive structures were found to be colocalized with non-activated, ramified microglia, suggesting that Abeta does not trigger microglial activation. — The findings reported here strongly argue against the hypothesis that neuroinflammatory changes contribute to AD dementia. Instead, they offer an alternative hypothesis of AD pathogenesis that takes into consideration: (1) the notion that microglia are neuron-supporting cells and neuroprotective; (2) the fact that development of non-familial, sporadic AD is inextricably linked to aging. They support the idea that progressive, aging-related microglial degeneration and loss of microglial neuroprotection rather than induction of microglial activation contributes to the onset of sporadic Alzheimer’s disease.” Our old friend/enemy cellular senescence seems to be the villain again.
A number of approaches have been successful in clearing out beta amyloid plaques in small-animal models of AD.
Clearing amyloid-beta plaque using IL-6
The October 2009 publication Massive gliosis induced by interleukin-6 suppresses AÎ² deposition in vivo: evidence against inflammation as a driving force for amyloid deposition seems to offer the most dramatic result and conclusion. The abstract starts out “Proinflammatory stimuli, after amyloid Î² (AÎ²) deposition, have been hypothesized to create a self-reinforcing positive feedback loop that increases amyloidogenic processing of the AÎ² precursor protein (APP), promoting further AÎ² accumulation and neuroinflammation in Alzheimer’s disease (AD). Interleukin-6 (IL-6), a proinflammatory cytokine, has been shown to be increased in AD patients implying a pathological interaction.” The experiment resulted in an opposite result, where in mice overexpression of IL-6 in mouse brains with amyloid plaques unexpectedly resulted in massive clearing out of the amyloid. As pointed out in a ScienceDaily release “ — the researchers over-expressed IL-6 in the brains of newborn mice that had yet to develop any amyloid plaques, as well in mice with pre-existing plaques. Using somatic brain transgenesis technology, scientists analyzed the effect of IL-6 on brain neuro-inflammation and plaque deposition. In both groups of mice, the presence of IL-6 lead to the clearance of amyloid plaques from the brain. Researchers then set out to determine exactly how IL-6 worked to clear the plaques and discovered that the inflammation induced by IL-6 directed the microglia to express proteins that removed the plaques. This research suggests that manipulating the brain’s own immune cells through inflammatory mediators could lead to new therapeutic approaches for the treatment of neurodegenerative diseases, particularly Alzheimer’s disease(ref).” IL-6 expression, previously thought to be a major part of the problem in AD is now seen to be potentially part of the solution. As far as I know, there has been no human experimentation yet involving treatment of AD using IL-6.
Clearing amyloid-beta plaque using granulocyte colony stimulating factor
The September 2009 publication Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer’s mice and the April 2009 publication Powerful beneficial effects of macrophage colony-stimulating factor on beta-amyloid deposition and cognitive impairment in Alzheimer’s disease suggest another approach to clearing out beta-amyloid plaques. “Together these results provide compelling evidence that systemic M-CSF administration is a powerful treatment to stimulate bone marrow-derived microglia, degrade Abeta and prevent or improve the cognitive decline associated with Abeta burden in a mouse model of Alzheimer’s disease(ref).” Again, as far as I know use of granulocyte colony stimulating factor (GCSF) for treating AD has not yet proceeded to the clinical testing stage for humans with AD. Clinical trials could proceed fairly quickly however, since GCSF is an approved substance used for other medical purposes. “GCSF is a blood stem cell growth factor or hormone routinely administered to cancer patients whose blood stem cells and white blood cells have been depleted following chemotherapy or radiation. GCSF stimulates the bone marrow to produce more white blood cells needed to fight infection. It is also used to boost the numbers of stem cells circulating in the blood of donors before the cells are harvested for bone marrow transplants. Advanced clinical trials are now investigating the effectiveness of GCSF to treat stroke, and the compound was safe and well tolerated in early clinical studies of ischemic stroke patients(ref).”
Clearing amyloid-beta plaque using monoclonal antibodies
Back in 2003 it was reported “Researchers from Lilly Research Laboratories and Elan Pharmaceuticals, among other laboratories, are working on a novel method for reversing the damage caused by amyloid plaques. They have found that certain monoclonal antibodies bind to beta amyloid and clear it from the brain. In experiments with mice engineered to develop Alzheimer’s-like symptoms, scientists from Lilly demonstrated that treatment with the monoclonal antibody m266, called “passive immunization,” not only cleared beta amyloid from the brains of the mice but also reversed some of their memory problems.” Now, seven years later, two monoclonal antibody substances solanezumab (Lilly) and bapineuzumab (Elan) are in Phase III clinical trials. “Bapineuzumab is a humanized monoclonal antibody, which binds to and clears beta-amyloid peptide, and is designed to provide antibodies to beta amyloid directly to the patient(ref).”
There are many more research and drug developments related to AD than I can cover here. The clinical trials database for AD shows 62 trials that are currently recruiting. Where does this all leave me?
- First of all, I am glad to see the new insights implicating senescence of microglia as a probably cause of AD. The new viewpoint brings us back yet-again to the central issue of aging and the importance of preventing age-related cellular senescence. Alzheimer’s disease is age related. If we can find ways to slow down aging, those ways will in themselves delay occurrences of AD. If we could stop aging, we could eradicate almost all AD. Let’s keep our eye on the ball that really counts.
- In this context I am glad to see renewed emphasis on prevention rather than cure of AD. “Within the last few years, the focus of the Alzheimer’s disease research community has shifted from seeking a cure for the disease to concentrating on prevention. The National Institutes of Health have earmarked more research funding for research centers investigating prevention, and some scientists believe that effective means of preventing the disease may be available within a decade(ref).” Sooner or later it should become obvious that effective measures to prevent AD will most likely help prevent a lot of other age-related diseases as well and in fact will be measures to slow or prevent aging.
- Current clinical trials of monoclonal antibodies will likely result in better means for control of beta-amyloid plaques and control of AD disease progression, but not cures for the disease itself which is most-likely caused by microglial cell senescence. I conjecture that the same will probably be true for other plaque-removing therapies using GCSF or IL-6.
- Based on what we know now, the two most promising general avenues for preventing microglial cell senescence are approaches to preserving or extending telomere lengths in microglia, and approaches to refreshing and reinvigorating the somatic stem cells which differentiate into microglia. I have discussed such approaches extensively in this blog and will continue to do so. They relate directly to the Telomere Shortening and Damage and the Stem Cell Supply Chain Breakdown theories of aging.