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Exercise as a strategy to prevent APOE ε4 ‐dependent phenotypes: Genetics/genetic factors of Alzheimer's disease
Abstract Background Human data suggest cerebrovascular dysfunction precedes and exacerbates Alzheimer’s disease (AD). APOE ε4 contributes to cerebrovascular decline with age, and APOE status interacts with angiogenesis pathways including the VEGF family to modify cognitive decline. However, the prec...
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| Published in: | Alzheimer's & dementia 2020-12, Vol.16 (S2) |
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| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
| Online Access: | Get full text |
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| Summary: | Abstract
Background
Human data suggest cerebrovascular dysfunction precedes and exacerbates Alzheimer’s disease (AD).
APOE
ε4
contributes to cerebrovascular decline with age, and APOE status interacts with angiogenesis pathways including the VEGF family to modify cognitive decline. However, the precise nature of this relationship is not known. Research suggests that running provides substantial health benefits that reduce risk for AD. Previous data from our lab showed that, transcriptionally, cerebrovascular processes such as vascular remodeling and angiogenesis terms can be altered short term running in young mice. Here, we are combining human and mouse studies to (i) understand the relationship between APOE status and the VEGF pathway in AD, and (ii) determine whether the effects of exercise on the cerebrovasculature are modified by
APOE
status.
Method
To assess cerebrovascular health, we took several approaches: (i) transcriptional profiling, (ii) immunofluorescence of basement membrane, and (iii) immunofluorescence of leakage (fibrin). To assess exercise and metabolic differences,
B6.APOE
ε4/ε4
(risk) and
B6.APOE
ε3/ε3
(neutral) mice were run from 1‐4 months (mo) and 1‐12mos, as well as metabolic phenotyping including circulating plasma lipid levels, food intake, water loss, running speed, and gas exchange. Heterozygous
B6.APOE
ε3/ε4
mice are included to evaluate the potential hypomorphic/ hypermorphic function of the
APOE
ε4
allele on cerebrovascular health. Human data from ROSMAP and ADNI cohorts is being compared to mouse data.
Result
Cerebrovascular dysfunction was evaluated in 2mo and 12mo
B6.APOE
ε3/ε3
and
APOE
ε4/ ε4
mice for basement membrane coverage and fibrin leakage which revealed an increase in COL4 and increased leakage, in 12mo female
APOE
ε4
/
ε3
compared to
B6.APOE
ε3/ε3
mice. Analysis of 1‐4mo running data showed no transcriptional evidence that the cerebrovasculature was altered in young
APOE
ε4
or
APOE
ε3
carriers, suggesting longer term interventions are necessary. Human data shows patients that suffer a more severe cognitive decline have increasing levels of angiogenesis markers in the brain and blood. Our ongoing work aims to identify the mechanism between
APOE
ε4
and angiogenesis/cerebrovascular integrity.
Conclusion
Recreated
APOE
ε4
mice recapitulate age‐dependent cerebrovascular deficits however running at a young timepoint will likely not affect cerebrovascular health. Longer term studies are underway to determine whether ch |
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| ISSN: | 1552-5260 1552-5279 |
| DOI: | 10.1002/alz.045887 |