Alzheimer's disease (AD), the most common dementing disorder of late life, is a major cause of disability and death in the elderly. AD is characterized and diagnosed by distinctive neuropathological alterations including extracellular deposits of the ?-amyloid (A?) peptide. Epidemiological investigations have demonstrated that AD is a complex, age-related disorder with numerous proposed genetic and environmental etiologies. Human genetic studies have shown that altered dosage and mutations in the amyloid precursor protein gene as well as mutations in presenilin 1 and presenilin 2 genes all cause early-onset AD, while the APOE gene is major risk factor in late-onset AD. Considerable evidence suggests that these genetic factors alter A? metabolism and/or A? deposition. However, the AD genes identified thus far account for less than 30% of genetic risk for AD. Due to the inherent variability and genetic heterogeneity in late-onset neurodegenerative disorders, the identification of the remainder of the genetic and environmental factors that modulate AD risk have proven extremely difficult. Over the past decade and a half, several groups, including our own, have focused on the development of accurate and defined mouse models of AD, in which both the genetic background and environmental exposure can be precisely and reproducibly modified in an effort to gain insight into factors that modify APP processing, the production and deposition of A? peptides, the onset of dementia and the neuropathological abnormalities that occur in AD. In the previous funding period of this grant application, we generated congenic strains, in which a human AD transgene was transferred into different inbred mouse strains. We subsequently characterized the effects of different inbred genetic backgrounds and specific genetic alterations on A? metabolism and deposition and other AD phenotypes and identified unique mouse genetic loci that regulate metabolism and deposition. In addition, in preliminary studies we determined that the effects of an environmental factor, namely high-fat/high-cholesterol diets, on brain A? levels are dependent upon the genetic background of the mice. The current studies seek to expand and extend these studies with a focus on genetic and environmental factors that regulate A? metabolism and deposition in two inbred mouse strains with the most divergent A? phenotypes, C57BL/6J and A/J, using the unique genetic resources available for these strains.
The specific aims of the current proposal are to: 1) Identify mouse chromosomes with gene(s) that regulate A? metabolism and deposition. 2) Identify and characterize genetic loci that regulate A? deposition. 3) Characterize genetic loci responsible for diet-induced alterations in A? metabolism and deposition.

Public Health Relevance

Human genetic studies have demonstrated that accumulation and aggregation of small peptide fragments, termed beta-amyloid, is central to the disease mechanisms underlying Alzheimer's disease, a major cause of death and disability in the elderly. However, it remains unclear how the multitude of postulated genetic and environmental risk factors for human AD directly influence the production and aggregation of beta-amyloid. The current studies seek to identify and characterize additional genetic and environmental (namely high-fat/high-cholesterol diets) factors influence beta-amyloid generation and deposition within the brains of transgenic mouse models of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG023012-10
Application #
8486347
Study Section
Special Emphasis Panel (ZRG1-BDCN-J (03))
Program Officer
Petanceska, Suzana
Project Start
2003-12-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2013
Total Cost
$289,425
Indirect Cost
$105,078
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Mlodzianoski, Michael J; Cheng-Hathaway, Paul J; Bemiller, Shane M et al. (2018) Active PSF shaping and adaptive optics enable volumetric localization microscopy through brain sections. Nat Methods 15:583-586
Bemiller, Shane M; Maphis, Nicole M; Formica, Shane V et al. (2018) Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy. J Neuroinflammation 15:278
Maphis, Nicole M; Jiang, Shanya; Binder, Jessica et al. (2017) Whole Genome Expression Analysis in a Mouse Model of Tauopathy Identifies MECP2 as a Possible Regulator of Tau Pathology. Front Mol Neurosci 10:69
Bemiller, Shane M; McCray, Tyler J; Allan, Kevin et al. (2017) TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener 12:74
Maphis, Nicole; Jiang, Shanya; Xu, Guixiang et al. (2016) Selective suppression of the ? isoform of p38 MAPK rescues late-stage tau pathology. Alzheimers Res Ther 8:54
Andreasson, Katrin I; Bachstetter, Adam D; Colonna, Marco et al. (2016) Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem 138:653-93
Maphis, Nicole; Xu, Guixiang; Kokiko-Cochran, Olga N et al. (2015) Loss of tau rescues inflammation-mediated neurodegeneration. Front Neurosci 9:196
Jay, Taylor R; Miller, Crystal M; Cheng, Paul J et al. (2015) TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med 212:287-95
Maphis, Nicole; Xu, Guixiang; Kokiko-Cochran, Olga N et al. (2015) Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138:1738-55
Komuro, Yutaro; Xu, Guixiang; Bhaskar, Kiran et al. (2015) Human tau expression reduces adult neurogenesis in a mouse model of tauopathy. Neurobiol Aging 36:2034-42

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