In the past PPG term, we have unequivocally linked the genes causing early onset Alzheimer's disease (AD) directly to functions'within endocytic and autophagic pathways of the lysosomal system, documenting specific impairment of these functions beginning at the earliest stages of AD. We propose to validate further our novel conceptual framework that positions the lysosomal system as a common primary target for disruption by diverse genetic and environmental AD-risk factors. Preliminary data support the working hypothesis that cumulative """"""""hits"""""""" to multiple sites within the endocytic and autophagy pathways in AD cause selective failures of vesicular retrograde transport and signaling, impaired clearance of pathogenic proteins including AP, neurotic dystrophy, and neurodegeneration. The four Projects apply a tightly integrated multidisciplinary approach to study the highly dynamic interplay among lysosome pathway compartments. Individual Projects focus mainly on distinct facets of the entire lysosomal system - the biological and genetic regulation of early endosome signaling (Projects 1, 4 respectively), late endosome/exosome biology (Project 3), and autophagy/lysosome function (Project 2) - thus enabling us to define comprehensively how specific major AD-risk factors disrupt the lysosomal system with significant pathogenic consequences. Innovative technologies from single-neuron gene profiling to video microscopy and high voltage immunogold EM imaging will be applied to patient cells and our novel mouse models. In addition to defining the mechanisms underlying pathobiology induced by key AD-risk factors (APP, cholesterol, presenilin, cystatin C, neurotrophin deprivation), we will provide the rationale and validation for innovative therapeutic approaches to AD, including modulators of endocytosis and lipid-mediated AD pathologies (Project 1), autophagy/lysosomal remediation (Project 2), exosome-based modulation and cystatin C-based therapies (Project 3), and drug target identification within APP/neurotrophin signaling pathways promoting neuron survival (Project 4). Validation for one or more of these new approaches will have significant impact on realizing therapeutics for AD and other major aging-related neurodegenerative diseases.

Public Health Relevance

Addressing an urgent need for additional perspectives on effective therapies for Alzheimer's Disease, our Program advances a novel biological framework for understanding how AD develops and that identifies new directions for the therapy of AD and possibly other aging-related diseases. Exploiting this framework, we propose to validate multiple innovative therapeutic approaches for AD. REVIEW OF INDIVUDUAL COMPONENTS CORE A: ADMINISTRATIVE CORE;Dr. Ralph A. Nixon, Core Leader (CL) DESCRIPTION (provided by applicant): Core A will facilitate the research aims of all projects and cores by providing all necessary administrative support, by fostering collaborative interactions and cross-fertilization of ideas across projects/cores, by facilitating education/training, and recruitment activities, and by providing for internal and external scientific review of the research. To achieve these objectives, the core will: 1) Monitor fiscal activities of the projects and cores, and centralize the administration of clerical and personnel matters. 2) Facilitate communication among investigators within the Program by holding monthly meetings to discuss progress made in each Program component. Communication and quality control will also be enhanced by a system of internal review of research findings prepared for progress reports and manuscripts. 3) Enhance ongoing scientific education and training of Program investigations through a range of seminar series, each involving a multidisciplinary selection of New York area and national/international speakers from the Alzheimer's disease research fields, the neurosciences, and neuroimaging, respectively. 4) Provide for ongoing scientific review of accomplishments, activities, and future directions of this Program Project by an External Advisory Committee of scientific experts. 5) Provide statistical consultation and develop new statistical methodologies as necessary. 6) Identify, recruit and mentor new investigators and trainees whose research can contribute to the long-range aims of this Program Project. Facilitate the use of resources generated through this Program by other investigators.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017617-13
Application #
8534648
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6 (01))
Program Officer
Petanceska, Suzana
Project Start
2000-02-15
Project End
2016-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
13
Fiscal Year
2013
Total Cost
$1,867,316
Indirect Cost
$685,245
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
Li, Wei; Sultana, Nargis; Siraj, Nabeel et al. (2016) Autophagy dysfunction and regulatory cystatin C in macrophage death of atherosclerosis. J Cell Mol Med 20:1664-72
Mathews, Paul M; Levy, Efrat (2016) Cystatin C in aging and in Alzheimer's disease. Ageing Res Rev 32:38-50
Rosa, Elyse; Mahendram, Sujeivan; Ke, Yazi D et al. (2016) Tau downregulates BDNF expression in animal and cellular models of Alzheimer's disease. Neurobiol Aging 48:135-142
Colacurcio, Daniel J; Nixon, Ralph A (2016) Disorders of lysosomal acidification-The emerging role of v-ATPase in aging and neurodegenerative disease. Ageing Res Rev 32:75-88
Strupp, Barbara J; Powers, Brian E; Velazquez, Ramon et al. (2016) Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer's Disease. Curr Alzheimer Res 13:97-106
Rao, Mala V; Campbell, Jabbar; Palaniappan, Arti et al. (2016) Calpastatin inhibits motor neuron death and increases survival of hSOD1(G93A) mice. J Neurochem 137:253-65
Tiernan, Chelsea T; Ginsberg, Stephen D; Guillozet-Bongaarts, Angela L et al. (2016) Protein homeostasis gene dysregulation in pretangle-bearing nucleus basalis neurons during the progression of Alzheimer's disease. Neurobiol Aging 42:80-90
Kim, S; Sato, Y; Mohan, P S et al. (2016) Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease. Mol Psychiatry 21:707-16
Jiang, Ying; Rigoglioso, Andrew; Peterhoff, Corrinne M et al. (2016) Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF. Neurobiol Aging 39:90-8
Morales-Corraliza, Jose; Wong, Harrison; Mazzella, Matthew J et al. (2016) Brain-Wide Insulin Resistance, Tau Phosphorylation Changes, and Hippocampal Neprilysin and Amyloid-β Alterations in a Monkey Model of Type 1 Diabetes. J Neurosci 36:4248-58

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