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| First Name: | Michael | | Last Name: | Myre | | Advanced Degrees: | PhD | | Affiliation: | MGH/Harvard Medical School | | Department: | Neurology | Country/Territory: | U.S.A. | | Email Address: |  |
Disclosure:
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Member reports no financial or other potential conflicts of interest. [Last Modified: 1 November 2007]
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View all comments by Michael Myre
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Alzheimer Disease, Polyglutamine Disorders (Huntington's, etc.)
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Animal Models, Apoptosis/Cell cycle, DNA microarrays, Drug screening, Epidemiology, A-beta PP/A-beta, Molecular and Cell biology, Neurobiology, Proteomics, Signal transduction
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Research institute, Medical hospital
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The role of epigenetic factors that contribute to Alzheimer's disease. Although mutations to the genes encoding APP, PS1/2 and APOE4 are intimately linked to developing AD or increasing the risk of developing AD, they represent the vast minority of AD cases. Coupled with the fact that animal models (e.g mice) of a human disease have been difficult to create, and display a substantial level of variability suggests that AD disease-genes alone may not be solely responsible for the pathogensis of early onset AD. Mutated genes in combination with epigenetic factors remain largely unexplored. |
Aberrant cell-cycle activation in postmitotic neurons and the role they might play in the initiation of pathological mechanisms leading to neurodegenerative signaling cascades. |
Dysregulation of critical cell cycle checkpoint proteins that control progression of G0/G1 into S-phase contribute to the cell cycle re-entry phenotype seen in AD brain and initiates the amyloidogenic cascade.
Cell cycle abnormalities in distinct neuronal populations suggest a breach into S-phase and G2. This hypothesis is the only scenario that can unify the observed pathological changes in AD brain (e.g. increased Abeta levels, increased phosphorylation of APP, increased phosphorylation of Tau, inflammatory response, increased reactive oxidative species (ROS) and apoptosis).
Could AD be a "reverse" form of neuronal cancer? If mutant APP and/or PS1/2 proteins increase apoptosis, it could conceivably limit our ability to detect changes in the levels of Abeta production in sera etc. as is typically the case. The one organ in which this effect would be intolerable is the non-proliferative, fully-differentiated brain.
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The current dogma that mature neurons cannot divide is a substantial obstacle. However, it does not exclude the possibility that mature neurons can be triggered into apoptosis. This in itself would be a deleterious event, and as such, neurons exhibit very strong anti-apoptotic mechansims. In terms of evolution, this neuronal phenotype would be expected to be beneficial since the accumulation of multiple head trauma events throughout life would lead to varying degrees of neuronal impairment.
As such, many pieces of evidence are missing, and will take time to acquire as technology advances. |
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