This application represents the first competing renewal of our program project, which uses an interdisciplinary team approach to address the unifying hypothesis that most, if not all, aging-related neurodegenerative disorders are caused by the intracellular or extracellular accumulation of specific proteins that have assumed pathogenic conformational states (proteinopathies). The resulting neurodegenerative disorders, which include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD) and other Lewy body diseases (LED), remain largely untreatable and represent a complex biomedical, behavioral and social problem. Medical breakthroughs are urgently needed in this area, and the surest way to such breakthroughs is to determine how exactly these diseases result in the dysfunction and degeneration of nerve cells. Our program addresses this important need by bringing together investigators with diverse areas of expertise, widely overlapping interests in proteinopathies, and an established track record of fruitful collaborative interactions. Our approach takes advantage of a great number of valuable resources and technologies, including robotic microscopy, molecular imaging, genetically engineered mouse models, RNAi mediated gene silencing, and cell type-specific expression of mechanistically informative viral constructs. Using these and other strategies, we will study the processes by which diverse proteins impair neuronal function and survival and compare our results to determine whether there are common mechanisms of neurodegeneration. We will also study the susceptibility of different neuronal populations to common versus disease-specific pathogenic processes to elucidate why these diseases so selectively attack specific neuronal populations. Project 1, "Mechanisms of Cell-Specific Huntingtin-lnduced Neurodegeneration" aims to elucidate cell autonomous and cell non-autonomous mechanisms that contribute to the susceptibility of striatal neurons to mutant huntingtin. Project 2, "Microglial Kynurenine Pathway and Selective Neuronal Vulnerability," will test if genetic or pharmacological inhibition of the microglial kynurenine pathway is protective in mouse models of AD and HD. Project 3, "Apolipoprotein E in Alzheimer's Disease: Cellular Mechanisms," will study the regulation of apolipoprotein E expression in neurons and explore Apin dependent roles of different apolipoprotein E isoforms in the pathogenesis of AD. Project 4, "Causes and Consequences of a-Synuclein Aggregation," will assess in combined models of AD and PD if interactions between a-synuclein and A? lead to neurodegeneration of specific neuronal populations through activation of glutamate receptors and proteases that cleave a-synuclein. Project 5, "Mechanisms of Aft-Induced Neuronal Deficits," will test whether the modulation of specific neuronal or glial molecules can block aberrant neuronal overexcitation and ameliorate behavioral abnormalities in mouse models of AD and other proteinopathies. The Cores (A: Administrative, B: Tissue Culture, C: Animal, D: Microscopy/Neuropathology) will provide the common services necessary to accomplish the goals of the program project. Our studies will shed light on diverse neurodegenerative diseases and could provide the knowledge needed to better treat and prevent them.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG022074-10
Application #
8286964
Study Section
Special Emphasis Panel (ZAG1-ZIJ-3 (J3))
Program Officer
Refolo, Lorenzo
Project Start
2003-06-15
Project End
2013-11-30
Budget Start
2012-06-01
Budget End
2013-11-30
Support Year
10
Fiscal Year
2012
Total Cost
$1,943,801
Indirect Cost
$783,222
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158
Eleuteri, Simona; Di Giovanni, Saviana; Rockenstein, Edward et al. (2015) Novel therapeutic strategy for neurodegeneration by blocking A? seeding mediated aggregation in models of Alzheimer's disease. Neurobiol Dis 74:144-57
Dhungel, Nripesh; Eleuteri, Simona; Li, Ling-Bo et al. (2015) Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on ?-synuclein. Neuron 85:76-87
Overk, Cassia R; Cartier, Anna; Shaked, Gideon et al. (2014) Hippocampal neuronal cells that accumulate ?-synuclein fragments are more vulnerable to A? oligomer toxicity via mGluR5--implications for dementia with Lewy bodies. Mol Neurodegener 9:18
Spencer, Brian; Emadi, Sharareh; Desplats, Paula et al. (2014) ESCRT-mediated uptake and degradation of brain-targeted ?-synuclein single chain antibody attenuates neuronal degeneration in vivo. Mol Ther 22:1753-67
Tsigelny, Igor F; Sharikov, Yuriy; Kouznetsova, Valentina L et al. (2014) Structural diversity of Alzheimer's disease amyloid-* dimers and their role in oligomerization and fibril formation. J Alzheimers Dis 39:583-600
Ubhi, Kiren; Rockenstein, Edward; Kragh, Christine et al. (2014) Widespread microRNA dysregulation in multiple system atrophy - disease-related alteration in miR-96. Eur J Neurosci 39:1026-41
Bomben, Valerie; Holth, Jerrah; Reed, John et al. (2014) Bexarotene reduces network excitability in models of Alzheimer's disease and epilepsy. Neurobiol Aging 35:2091-5
Lehmann, Manja; Ghosh, Pia M; Madison, Cindee et al. (2014) Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients. J Neurol Neurosurg Psychiatry 85:266-73
Overk, Cassia R; Masliah, Eliezer (2014) Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease. Biochem Pharmacol 88:508-16
Knoferle, Johanna; Yoon, Seo Yeon; Walker, David et al. (2014) Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice. J Neurosci 34:14069-78

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