Amyloid and inflammation: modulation by apoE, gender, air pollution, and drugs. We propose to test novel inflammation-gender-environment interactions on brain amyloid and microbleeds (microhemorrhages) in mouse models for Alzheimer disease (AD) and aging. The highest AD risk group, women apoE4 carriers, is modelled in EFAD mice carrying familial dominant AD genes in combination with human apoE alleles (targeted replacement, ApoE-TR). Female E4FAD mice have the most brain cytokine induction, amyloid peptide (Abeta) accumulation, and microbleeds (pilot data). In humans, cerebral microbleeds are most prevalent in apoE4 carriers, and are associated with higher conversion to clinical AD. Among environmental influence on cognitive aging and AD, urban air pollution is also considered in an experimental model with nano-scale particulate matter (nPM) from an urban traffic air corridor (with Constantinos Sioutas, co-Investigator). The nPM of well-characterized composition are re-aerosolized for controlled exposure of mice. Pilot data show EFAD mice respond with apoE allele specificity.
Aim 1 addresses the age schedule of emergence of gender-apoE allele interactions in AD phenotypes during postnatal development and aging. EFAD brains will be studied for inflammatory responses (TNFa, microglia); for APP processing and Abeta deposits; for cerebrovascular amyloid and microbleeds; and for spatial memory (with Christian Pike, co-Investigator). Sex differences will be manipulated by neonatal steroid treatment to test the hypothesis that excess expression of Abeta, in either genetic sex, will drive the level of inflammation and microbleeds. In vitro, EFAD microglia will be studied for apoE-sex interactions on inflammatory gene expression.
Aim 2 examines air pollution nPM effects in female EFAD mice by dose and time on accelerating brain inflammation and AD phenotypes. Critical ages of nPM exposure for AD-phenotypes will be examined with findings from Aim 1 for the earliest age showing gender differences in AD-phenotypes. We can only test one sex because nPM treatment doubles the number of variables. We prioritize females in this aim since females are the highest AD risk group. However, in vitro studies of microglia and neurons from adult brains will include both sexes for nPM induced inflammatory and pro-amyloidogenic responses.
Aim 3 examines a drug intervention for brain inflammation and microbleeds by a novel gamma secretase modulator to attenuate Abeta synthesis. Drug-treated female EFAD mice will be exposed to chronic nPM and examined for apoE interactions on AD-phenotypes.

Public Health Relevance

Air pollution is associated with cognitive decline and brain inflammation and may be an Alzheimer risk factor. Mice with the major human genetic risk factors (apoE4 and female) will be analyzed for air pollution sensitivity to inflammation, and drug interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
1RF1AG051521-01
Application #
9001756
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Wise, Bradley C
Project Start
2015-09-30
Project End
2020-08-31
Budget Start
2015-09-30
Budget End
2020-08-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Other Specialized Schools
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90032
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Cacciottolo, Mafalda; Christensen, Amy; Moser, Alexandra et al. (2016) The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice. Neurobiol Aging 37:47-57
Finch, Caleb E; Crimmins, Eileen M (2016) Constant molecular aging rates vs. the exponential acceleration of mortality. Proc Natl Acad Sci U S A 113:1121-3

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