Principal Investigators

    NIXON, RALPH A.

    Institution

    NATHAN S. KLINE INSTITUTE FOR PSYCH RES

    Contact information of lead PI

    Country

    USA

    Title of project or programme

    CELL AND MOLECULAR PATHOBIOLGY OF ALZHEIMERS DISEASE

    Source of funding information

    NIH (NIA)

    Total sum awarded (Euro)

    € 9,547,389.91

    Start date of award

    15/02/2000

    Total duration of award in years

    15

    The project/programme is most relevant to:

    Alzheimer's disease & other dementias

    Keywords

    Acquired Cognitive Impairment... Aging... Alzheimer's Disease... Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)... Brain Disorders... Dementia... Neurodegenerative... Neurosciences... Prevention

    Research Abstract

    DESCRIPTION (provided by applicant) 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.

    Lay Summary

    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.

    Further information available at:

Types: Investments > €500k
Member States: United States of America
Diseases: Alzheimer's disease & other dementias
Years: 2016
Database Categories: N/A
Database Tags: N/A

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