The use of transgenic animals is a powerful and informative approach that has been successfully undertaken by Core B in previous cycles to study neurodegenerative diseases. Core B will provide Projects 1-4 with appropriately genotyped and aged mouse models of endosomal-autophagic-lysosomal system abnormalities observed in Alzheimer's disease (AD) and Down's syndrome (DS). Core B will also serve to identify novel animal models with these pathologies, and to generate novel crosses between these models, and either transgenic or knockout models that carry or lack genes expected to affect AD-related pathologies. Endosomal abnormalities are the earliest known pathology in AD, preceding AB deposition and, in human DS, can be detected in neurons even before birth. As a model of endosomal pathology we are using the Ts2 trisomic mouse, which we have identified as a model with pathologies similar to Ts65Dn mice yet with important breeding and transmission advantages. Among models used to examine endosomal and autophagic-lysosomal system pathologies are transgenic mice expressing human rab5, XI la, mutant presenilin 1, and knockout mice for presenilin 1. Models of either B-amyloidosis and amyloid p precursor protein (APP) overexpression or knockout are used to examine the effect of APP and APP metabolites on endocytosis and lysosomal system function. Additionally, in order to identify protective effects of cystatin C, which the core leader has shown to affect disease processes, mouse models with endosomal and autophagic-lysosomal system pathologies will be crossed with either transgenic or knockout mice for cystatin C. The Core Leader has extensive experience managing a large mouse colony with complex breeding schemes, and will be able to coordinate animal breeding, genotyping, and delivery to Projects 1-4.

Public Health Relevance

The use of genetically engineered animals is a powerful and informative approach to study neurodegenerative diseases such as Alzheimer's disease (AD). This Core provides models to study age related progress of specific pathologies observed in the human AD, to identify genes and environmental factors that affect disease processes, and to develop potential therapies for AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017617-14
Application #
8724301
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
14
Fiscal Year
2014
Total Cost
$226,218
Indirect Cost
$85,937
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
Alldred, Melissa J; Lee, Sang Han; Petkova, Eva et al. (2015) Expression profile analysis of vulnerable CA1 pyramidal neurons in young-Middle-Aged Ts65Dn mice. J Comp Neurol 523:61-74
Alldred, Melissa J; Lee, Sang Han; Petkova, Eva et al. (2015) Expression profile analysis of hippocampal CA1 pyramidal neurons in aged Ts65Dn mice, a model of Down syndrome (DS) and Alzheimer's disease (AD). Brain Struct Funct 220:2983-96
Kelley, Christy M; Powers, Brian E; Velazquez, Ramon et al. (2014) Sex differences in the cholinergic basal forebrain in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease. Brain Pathol 24:33-44
Counts, Scott E; Alldred, Melissa J; Che, Shaoli et al. (2014) Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology 79:172-9
Yan, Jian; Ginsberg, Stephen D; Powers, Brian et al. (2014) Maternal choline supplementation programs greater activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice. FASEB J 28:4312-23
Xue, Xue; Wang, Li-Rong; Sato, Yutaka et al. (2014) Single-walled carbon nanotubes alleviate autophagic/lysosomal defects in primary glia from a mouse model of Alzheimer's disease. Nano Lett 14:5110-7
Kaur, Gurjinder; Sharma, Ajay; Xu, Wenjin et al. (2014) Glutamatergic transmission aberration: a major cause of behavioral deficits in a murine model of Down's syndrome. J Neurosci 34:5099-106
Kelley, Christy M; Powers, Brian E; Velazquez, Ramon et al. (2014) Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young-adult Ts65Dn and disomic mice. J Comp Neurol 522:1390-410
Wesson, Daniel W; Morales-Corraliza, Jose; Mazzella, Matthew J et al. (2013) Chronic anti-murine Aýý immunization preserves odor guided behaviors in an Alzheimer's ýý-amyloidosis model. Behav Brain Res 237:96-102
Nixon, Ralph A (2013) The role of autophagy in neurodegenerative disease. Nat Med 19:983-97

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