1. Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology.
- Author
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Miller B, Kim SJ, Cao K, Mehta HH, Thumaty N, Kumagai H, Iida T, McGill C, Pike CJ, Nurmakova K, Levine ZA, Sullivan PM, Yen K, Ertekin-Taner N, Atzmon G, Barzilai N, and Cohen P
- Subjects
- Aged, 80 and over, Animals, Female, Humans, Male, Mice, Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Disease Models, Animal, Heterozygote, Intracellular Signaling Peptides and Proteins, Mice, Transgenic, Apolipoprotein E4 genetics, Apolipoprotein E4 metabolism, Brain metabolism, Brain pathology, Longevity genetics
- Abstract
The APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial-derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4. Utilizing an APOE4-centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid-beta accumulation compared to the wild-type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid-beta clearance. Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in APOE4-linked amyloidosis, underscoring its significance in longevity and cognitive health among APOE4 carriers., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
- Published
- 2024
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