Although multiple lines of evidence link beta-amyloid peptides to the pathogenesis of Alzheimer's disease, the molecular mechanism whereby beta-amyloid is involved remains unknown. Synaptic dysfunction is an early event in Alzheimer's disease and increasing evidence indicates that the aberrant accumulation of beta- amyloid within neurons is critical for synaptic dysfunction. Specifically, a triple transgenic mouse was described in which physiological alterations implicated in memory were altered with the onset of intraneuronal beta-amyloid accumulation and prior to plaques and tangles. Employing immuno-gold electron microscopy, we reported in transgenic mutant APR mice that develop age-related beta-amyloidosis the accumulation of beta-amyloid especially in late endosomal vesicles of distal processes and synaptic compartments, which at times were associated with subcellular morphological alterations consistent with degeneration. In a subsequent study, we demonstrated that beta-amyloid oligomerization begins within processes and synaptic compartments and is consistently linked with neurodegeneration. Moreover, we found by Western blot, immunofluorescence microscopy and immuno-electron microscopy that neurons from amyloid precursor protein (APR) mutant transgenic mice with time in culture paralleled the subcellular beta- amyloid accumulation and Alzheimer's disease-like synaptic alterations observed in brain in vivo. We hypothesize that intraneuronal beta-amyloid accumulation induces synaptic dysfunction by impairing multivesicular body sorting and the ubiquitin proteasome system in neurons. We propose studies in mutant APR transgenic neurons in culture to elucidate the biological mechanism leading to synaptic dysfunction. Our results indicate that mutant APR transgenic neurons have alterations in endocytosis, differential pre- and post-synaptic proteins and the ubiquitin proteasome system. A better understanding of the mechanism whereby beta-amyloid is involved in synaptic dysfunction and Alzheimer's disease pathogenesis may be important for devising more effective treatments for Alzheimer's disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG027140-02
Application #
7477682
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Snyder, Stephen D
Project Start
2007-08-01
Project End
2011-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
2
Fiscal Year
2008
Total Cost
$279,888
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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