Abstract

Alzheimer's disease (AD) is characterized clinically by dementia and neuropathologically by amyloid plaques, amyloid angiopathy, dystrophic neurites, NFT's, gliosis, and loss of neuronal subpopulations and synapses. Increasing evidence suggests that the AB peptide derived from APP plays a central role in AD. The goals of this project are to characterize neuronal and glial products that contribute to amyloidogenesis and neurodegeneration and identify cortical AD-related pathogenetic pathways that could be targeted by therapeutic interventions. Mice expressing a PDGF-promoter driven, alternatively spliced hAPP minigene, (PDGF-APP mice) develop several aspects of AD neuropathology. This proposal is to utilize this and related models to study cerebral amyloidogenesis and amyloid-induced neurodegeneration in vivo with the following aims: 1) Determine what factors influence AB production and B-amyloid deposition in vivo.; 2) Determine whether development of neuronal/synaptic degeneration in PDGF-hAPP mice depends on B-amyloid formation; 3) Determine whether B-amyloid in the brain results in aberrant induction of neuronal apoptosis and whether this process involves excitotoxic mechanisms.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG011385-07S1
Application #
6346700
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Snyder, D Stephen
Project Start
1992-09-01
Project End
2002-04-30
Budget Start
2000-09-30
Budget End
2001-04-30
Support Year
7
Fiscal Year
2000
Total Cost
$168,950
Indirect Cost

  Institution

Name
J. David Gladstone Institutes
Department
Type
DUNS #
047120084
City
San Francisco
State
CA
Country
United States
Zip Code
94158

  Publications

Huang, Timothy Y; Zhao, Yingjun; Jiang, Lu-Lin et al. (2017) SORLA attenuates EphA4 signaling and amyloid ?-induced neurodegeneration. J Exp Med 214:3669-3685
Spencer, Brian; Kim, Changyoun; Gonzalez, Tania et al. (2016) ?-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease. Hum Mol Genet 25:1100-15
Suberbielle, Elsa; Djukic, Biljana; Evans, Mark et al. (2015) DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nat Commun 6:8897
Rockenstein, Edward; Overk, Cassia R; Ubhi, Kiren et al. (2015) A novel triple repeat mutant tau transgenic model that mimics aspects of pick's disease and fronto-temporal tauopathies. PLoS One 10:e0121570
Zhao, Yingjun; Tseng, I-Chu; Heyser, Charles J et al. (2015) Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis. Neuron 87:963-75
Dewji, Nazneen N; Singer, S Jonathan; Masliah, Eliezer et al. (2015) Peptides of presenilin-1 bind the amyloid precursor protein ectodomain and offer a novel and specific therapeutic approach to reduce ß-amyloid in Alzheimer's disease. PLoS One 10:e0122451
Games, Dora; Valera, Elvira; Spencer, Brian et al. (2014) Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. J Neurosci 34:9441-54
Ettle, Benjamin; Reiprich, Simone; Deusser, Janina et al. (2014) Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells. Mol Cell Neurosci 62:68-78
Borlikova, Gilyana G; Trejo, Margarita; Mably, Alexandra J et al. (2013) Alzheimer brain-derived amyloid ýý-protein impairs synaptic remodeling and memory consolidation. Neurobiol Aging 34:1315-27
Games, Dora; Seubert, Peter; Rockenstein, Edward et al. (2013) Axonopathy in an ?-synuclein transgenic model of Lewy body disease is associated with extensive accumulation of C-terminal-truncated ?-synuclein. Am J Pathol 182:940-53

Showing the most recent 10 out of 86 publications