The final, formatted version of the article will be published soon.
ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 16 - 2024 |
doi: 10.3389/fnagi.2024.1415072
This article is part of the Research Topic APOE4-associated Heterogeneity in the Pathogenesis of Alzheimer's Disease View all 7 articles
Effects of obesogenic diet and 17-estradiol in female mice with APOE 3/3, 3/4 and 4/4 genotypes
Provisionally accepted- University of Southern California, Los Angeles, United States
The main genetic risk factor for Alzheimer's disease (AD) is the apolipoprotein E ε4 allele (APOE4). AD risk associated with APOE4 disproportionately affects women. Further, human and rodent studies indicate that the cognitive deficits associated with APOE4 are greater in females.One modifiable AD risk factor is obesity during middle-age. Given that about two-thirds of US adults are overweight, it is important to understand how obesity affects AD risk, how it interacts with APOE4, and the extent to which its detrimental effects can be mitigated with therapeutics.One intervention studied for women is estrogen-based hormone therapy, which can exert numerous health benefits when administered in early middle-age. No experimental studies have examined the interactions among APOE4, obesity, and hormone therapy in aging females. To begin to explore these issues, we considered how obesity outcomes are affected by treatment with estradiol at the onset of middle-age in female mice with human APOE3 and APOE4. Further, to explore how gene dosage affects outcomes, we compared mice homozygous for APOE3 (3/3) and homozygous (4/4) or hemizygous (3/4) for APOE4. Mice were examined over a four-month period that spans the transition into reproductive senescence, a normal age-related change that models many aspects of human perimenopause. Beginning at 5 months of age, mice were maintained on a control diet (10% fat) or high-fat diet (HFD; 60% fat). After 8 weeks, by which time obesity was present in all HFD groups, mice were implanted with an estradiol or vehicle capsule that was maintained for the final 8 weeks. Animals were assessed on a range of metabolic and neural measures. Overall, APOE4 was associated with poorer metabolic function and cognitive performance. However, obesogenic diet induced relatively greater impairments in metabolic function and cognitive performance in APOE3/3 mice. Estradiol treatment improved metabolic and cognitive outcomes across all HFD groups, with APOE4/4 generally exhibiting the greatest benefit. APOE3/4 mice were intermediate to the homozygous genotypes on many measures but also exhibited unique profiles. Together, these findings highlight the importance of of estradiol.
Keywords: APOE, estrogen, Metabolic impairment, lipidomics, Microglia, Obesity
Received: 09 Apr 2024; Accepted: 26 Aug 2024.
Copyright: © 2024 Christensen, Qian and Pike. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Christian J. Pike, University of Southern California, Los Angeles, United States
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.