Hypothalamus Amyloid Levels Are Associated with Early Sex-Dependent Alterations in Peripheral Energy Homeostasis in TgF344-AD Rats.

Overview

1. Neuroscience Institute, Petit Science Center, Georgia State University,PO Box 5030, Atlanta, GA 30302-5030 USA
2. Department of Human Genetics, Emory School of Medicine, Whitehead Biomedical Research Building,615 Michael St, Suite 301, Atlanta, GA 30322 USA
3. Department of Nutrition, Georgia State University,Urban Life Building, PO Box 4019, Atlanta, GA 30302-4019 USA
4. Center for Behavioral Neuroscience, Petit Science Center, Georgia State University,PO Box 5030, Atlanta, GA 30302-5030 USA
5. Human and Evolutionary Biology Section, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California,3616 Trousdale Parkway, AHF-252, Los Angeles, CA 90089-0372 USA
6. Department of Psychology, Georgia State University,Urban Life Building, 140 Decatur St, Atlanta, GA 30303-3083 USA

Abstract

We reported previously that diet-induced obesity exacerbates early-stage Alzheimer’s disease (AD)–like pathology in TgF344-AD rats. Those findings also suggested that they may be prone to weight gain during early AD development, raising the possibility of early hypothalamic dysfunction. In this study, we investigate this by determining whether hypothalamic soluble amyloid-β40 (Aβ40) and amyloid-β42 (Aβ42) are detectable during early AD development in TgF344-AD rats and whether their presence is associated with alterations in energy homeostasis. Energy intake, body composition, whole body glucose clearance, body temperature rhythms, interscapular brown adipose tissue (iBAT) mass, and iBAT expression of the thermogenic uncoupling protein 1 (UCP1) were assessed. The results demonstrate that Aβ40 and Aβ42 are detectable in the hypothalamus during the early stages of AD development and that hypothalamic but not cortical Aβ42 is associated with impaired glucose regulation in males and iBAT mass in females. Male TgF344-AD rats became heavier than wild-type (WT) littermates by 5 weeks of age, with a similar increase emerging later in females (~ 5 months). Female TgF344-AD rats consumed more chow and a high-fat high-sugar (HFHS) diet, gained more weight on that diet, and showed reduced UCP1, effects not seen in males. Both sexes exhibited elevated body temperatures. This increase was restricted to the dark phase in females, coinciding with excess caloric intake. Finally, HFHS feeding impaired glucose regulation in male but not female TgF344-AD rats. These findings suggest hypothalamic Aβ42 may contribute to sex-specific disruptions in peripheral energy homeostasis that may be an early symptom of AD development.

Supplementary Information: The online version contains supplementary material available at 10.1007/s12035-026-06014-4.

Reproduced under the paper's license (CC BY), from the paper cited above.

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• doi:10.17632/rthpp2ktb7.1, at the source; found in “Data Availability”

Data Availability

Data supporting the findings can be found online at Mendeley’s Data Repository with the 10.17632/rthpp2ktb7.1

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Publisher: n/a → Springer Science+Business Media
• Funding: added National Science Foundation: 2313253; National Institutes of Health: 1r34da061483-01, RO1DK114700, AG066511

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 5 keywords, 14 MeSH terms, 112 references.

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This paper

Levine, C. M., Caggiano, C., Anderson, T., Kelberman, M. A., Weinshenker, D., Lail, H. L., Wanders, D., Bangasser, D. A., Kanoski, S. E., & Parent, M. B. (2026). Hypothalamus Amyloid Levels Are Associated with Early Sex-Dependent Alterations in Peripheral Energy Homeostasis in TgF344-AD Rats. Molecular neurobiology, 63(1), 739. https://doi.org/10.1007/s12035-026-06014-4

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