Study summary · research use only
Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study combined analysis of human centenarian data, an APOE4-centric mouse model of amyloidosis (APP/PS1/APOE4), and in vitro experiments to investigate a humanin variant called P3S. Humanin is described as a mitochondrial-derived peptide comprising 24 amino acids. The authors report the P3S variant was enriched in centenarians carrying the APOE4 allele and showed strong affinity for APOE4 in silico and experimentally. In APOE4 mice, humanin P3S was associated with reduced brain amyloid-beta accumulation compared with wild-type humanin, and transcriptomic and in vitro data pointed to enhanced amyloid-beta phagocytosis as a possible mechanism. In the temporal cortex of human APOE4 carriers, humanin expression correlated with phagocytosis-related genes, and the authors describe P3S as more prevalent among individuals of Ashkenazi descent.
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.
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