Development and characterization of a novel Clusterin mouse model

Project: Research project

Description

? DESCRIPTION (provided by applicant): Alzheimer disease (AD) is the most common cause of dementia and is characterized by extracellular plaques formed by the deposition of amyloid-ß (Aß) peptide and intracellular tangles comprised of hyperphosphorylated forms of the tau protein. Another common pathology in AD is cerebral amyloid angiopathy (CAA), caused by Aß deposition in the walls of cerebral vessels leading to vascular dysfunction and hemorrhage. The strongest genetic risk factor for both AD and CAA is e4 allele of the apolipoprotein E (APOE) gene, but multiple recent genome-wide association studies have proven that a similar apolipoprotein, Clusterin (CLU), also confers risk for AD. While much is known about apoE biology, much less is known about CLU biology but several lines of evidence indicate that key differences may exist between human and mouse CLU protein. Studies from many years ago demonstrated that CLU is a critical factor in mediating the neurotoxicity associated with amyloid plaques in vivo through some unknown signaling mechanism. The objective of this application is to generate a novel humanized CLU mouse in which the entire human CLU locus replaces the endogenous mouse Clu locus. These mice will be characterized by behavioral, biochemical and histological methods at baseline as well as after immune challenge with lipopolysaccharide. This new mouse model will be useful not only for AD but also for stroke and breast cancer given the emerging role of CLU in those respective fields.
StatusFinished
Effective start/end date5/15/154/30/17

Funding

  • National Institutes of Health: $78,250.00
  • National Institutes of Health: $78,250.00

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Clusterin
Alzheimer Disease
Cerebral Amyloid Angiopathy
Apolipoproteins E
tau Proteins
Apolipoproteins
Genome-Wide Association Study
Amyloid Plaques
Amyloid
Blood Vessels
Lipopolysaccharides
Dementia
Stroke
Alleles
Pathology
Breast Neoplasms
Hemorrhage
Peptides
Genes

ASJC

  • Medicine(all)