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 #
5R01AG027140-04
Application #
7835702
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Refolo, Lorenzo
Project Start
2007-08-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$277,089
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
Willén, Katarina; Sroka, Agnieszka; Takahashi, Reisuke H et al. (2017) Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-? and Amyloid-? Protein Precursor with Synapses. J Alzheimers Dis 60:511-524
Gouras, Gunnar K; Willén, Katarina; Tampellini, Davide (2012) Critical role of intraneuronal A? in Alzheimer's disease: technical challenges in studying intracellular A?. Life Sci 91:1153-8
Majumdar, Amitabha; Capetillo-Zarate, Estibaliz; Cruz, Dana et al. (2011) Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes. Mol Biol Cell 22:1664-76
Capetillo-Zarate, Estibaliz; Gracia, Luis; Yu, Fangmin et al. (2011) High-resolution 3D reconstruction reveals intra-synaptic amyloid fibrils. Am J Pathol 179:2551-8
Tampellini, Davide; Rahman, Nawreen; Lin, Michael T et al. (2011) Impaired ?-amyloid secretion in Alzheimer's disease pathogenesis. J Neurosci 31:15384-90
Tampellini, Davide; Gouras, Gunnar K (2011) Analysis of vesicular trafficking in primary neurons by live imaging. Methods Mol Biol 793:343-50
Takahashi, Reisuke H; Capetillo-Zarate, Estibaliz; Lin, Michael T et al. (2010) Co-occurrence of Alzheimer's disease ß-amyloid and ? pathologies at synapses. Neurobiol Aging 31:1145-52
Tampellini, Davide; Capetillo-Zarate, Estibaliz; Dumont, Magali et al. (2010) Effects of synaptic modulation on beta-amyloid, synaptophysin, and memory performance in Alzheimer's disease transgenic mice. J Neurosci 30:14299-304
Tampellini, Davide; Gouras, Gunnar K (2010) Synapses, synaptic activity and intraneuronal abeta in Alzheimer's disease. Front Aging Neurosci 2:
Gouras, Gunnar K; Tampellini, Davide; Takahashi, Reisuke H et al. (2010) Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease. Acta Neuropathol 119:523-41

Showing the most recent 10 out of 12 publications