Presenilin 1 Mutations impair neuronal Bioenergetics and dietary Energy Restriction ameliorates cognitive Deficits caused by a Presenilin 1 Mutation

Monday, September 22, 2014 — Poster Session I
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NIA	NEURO-19

* FARE Award Winner

Authors

• C. Maharana
• R. Cutler
• B. Wustman
• A. Stevens
• M. P. Mattson

Abstract

Missense mutations in presenilin 1 (PS1) causes most early onset familial Alzheimer’s disease (EOFAD). PS1 is a transmembrane protein that forms catalytic site of gamma-secretase complex, but PS1 may also have gamma-secretase independent cellular functions. To elucidate the impact of PS1 mutations on cellular bioenergetics, a cell-based model with a human neuroglioma cell line engineered to express in an inducible manner wild type (WT) or AD-causing mutant forms of PS1. We observed PS1 mutations caused reduction in mitochondrial membrane potential, increased vulnerability to glucose deprivation-induced degeneration, and altered cellular respiratory capacity measured using Seahorse. We further applied dietary restrictions to WT and PS1mutKI mice in 3 groups; control (C), intermittent fasting (IF) or high calorie diet (HCD). We found, WT and PS1mutKI mice on IF diet exhibited improved spatial memory retention in water maze test and greater preference for the novel object in an object recognition test compared to mice on control diet. Contrarily, WT and PS1mutKI mice maintained on HCD exhibited increased anxiety, measured using open-field and elevated plus maze when compared to WT and PS1mutKI mice on C or IF diets. Thus, targeting neuronal bioenergetics by dietary intervention may have potential to counteract pathogenic actions of PS1 mutations.

back to top