This program focuses on newly identified features of AD pathobiology, having particular relevance to sporadic AD (SAD) and the role of vascular risk factors. The overall goal is to test the hypothesis that endocytic pathway (EP) and lysosomal system (LS) abnormalities, which include the earliest pathological changes yet demonstrated in SAD brain, are centrally involved in amyloidogenesis and neurodegeneration in SAD and are a critical link between vascular and parenchymal pathology in AD. The Program's main objectives are to elucidate underlying cellular mechanisms in AD by developing imporoved mouse models of AD, particular SAD, and of vascular pathology and by applying biochemical, cell biological, morphometric, and in vivo MR imaging approaches to these models. The first project investigate abnormalities of neuronal endocytosis and increased protease trafficking to early endosomes and purified endosome fractions will be analyzed in relation to disease onset and progression. Transfected cells and transgenic and mutant mice that model EP and protease trafficking alterations will be characterized to establish how these abnormalities influence Abeta formation and clearance and the survival of neurons and vascular endothelia. Another project tests the hypothesis that neuronal LS activation promotes cell atrophy and neurodegeneration. The onset and progression of LS activation in relation to other AD neuropathology and APOE genotype will be determined in SAD brain. Antecedents to LS activation and relationships to neuropathology will be evaluated in transgenic FAD mouse selectively modulated. Mechanisms underlying lysosome- mediated cell death will be defined. Another project, ischemia models and transgenic mouse models of cerebral amyloid angiopathy and of human APOE will be used to clarify how vascular injury and ApoE isotype modulate EP and LS abnormalities and promote AD neuropathology. Abeta clearance will be studied in vivo in AD and vascular mouse models and in vitro in organotypic models of the human and mouse BBB. The last project, longitudinal MR imaging will be applied to transgenic mouse models to characterize the effects of progressive beta-amyloid deposition on brain structure and function. The measures, which are directly translatable to human imaging studies and other mouse models, including brain regional volumes, cerebral perfusion (blood flow), and diffusion quantitative neuropathology. It is anticipated that this Program will establish improved animal models for drug discovery, advance clinical diagnosis by MR imaging, and define novel cellular mechanisms of pathogenesis that will be the basis for AD therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017617-02
Application #
6328651
Study Section
Special Emphasis Panel (ZAG1-BJS-3 (O1))
Program Officer
Snyder, D Stephen
Project Start
2000-02-15
Project End
2004-11-30
Budget Start
2001-01-01
Budget End
2001-11-30
Support Year
2
Fiscal Year
2001
Total Cost
$1,363,573
Indirect Cost
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
Lee, Ju-Hyun; Rao, Mala V; Yang, Dun-Sheng et al. (2018) Transgenic expression of a ratiometric autophagy probe specifically in neurons enables the interrogation of brain autophagy in vivo. Autophagy :1-15
Alldred, Melissa J; Chao, Helen M; Lee, Sang Han et al. (2018) CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation. Hippocampus 28:251-268
Jeanneteau, Freddy; Barrère, Christian; Vos, Mariska et al. (2018) The Stress-Induced Transcription Factor NR4A1 Adjusts Mitochondrial Function and Synapse Number in Prefrontal Cortex. J Neurosci 38:1335-1350
Peng, Katherine Y; Pérez-González, Rocío; Alldred, Melissa J et al. (2018) Apolipoprotein E4 genotype compromises brain exosome production. Brain :
Ginsberg, Stephen D; Alldred, Melissa J; Gunnam, Satya M et al. (2018) Expression profiling suggests microglial impairment in human immunodeficiency virus neuropathogenesis. Ann Neurol 83:406-417
Tiernan, Chelsea T; Ginsberg, Stephen D; He, Bin et al. (2018) Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease. Neurobiol Dis 117:125-136
Kaur, Gurjinder; Gauthier, Sebastien A; Perez-Gonzalez, Rocio et al. (2018) Cystatin C prevents neuronal loss and behavioral deficits via the endosomal pathway in a mouse model of down syndrome. Neurobiol Dis 120:165-173
Colacurcio, Daniel J; Pensalfini, Anna; Jiang, Ying et al. (2018) Dysfunction of autophagy and endosomal-lysosomal pathways: Roles in pathogenesis of Down syndrome and Alzheimer's Disease. Free Radic Biol Med 114:40-51
Pacheco-Quinto, Javier; Clausen, Dana; Pérez-González, Rocío et al. (2018) Intracellular metalloprotease activity controls intraneuronal A? aggregation and limits secretion of A? via exosomes. FASEB J :fj201801319R
East, Brett S; Fleming, Gloria; Peng, Kathy et al. (2018) Human Apolipoprotein E Genotype Differentially Affects Olfactory Behavior and Sensory Physiology in Mice. Neuroscience 380:103-110

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