SIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice

Abstract

Intermittent food deprivation (fasting, IF) improves mood and cognition and protects neurons against excitotoxic degeneration in animal models of epilepsy and Alzheimer’s disease (AD). The mechanisms by which neuronal networks adapt to IF and how such adaptations impact neuropathological processes are unknown. We show that hippocampal neuronal networks adapt to IF by enhancing GABAergic tone, which is associated with reduced anxiety-like behaviors and improved hippocampus-dependent memory. These neuronal network and behavioral adaptations require the mitochondrial protein deacetylase SIRT3 as they are abolished in SIRT3-deficient mice and wild type mice in which SIRT3 is selectively depleted from hippocampal neurons. In the App NL-G-F mouse model of AD, IF reduces neuronal network hyperexcitability and ameliorates deficits in hippocampal synaptic plasticity in a SIRT3-dependent manner. These findings demonstrate a role for a mitochondrial protein deacetylase in hippocampal neurons in behavioral and GABAergic synaptic adaptations to IF.

5‐Heptadecylresorcinol, a Biomarker for Whole Grain Rye Consumption, Ameliorates Cognitive Impairments and Neuroinflammation in APP/PS1 Transgenic Mice

“…[ 23,24 ] Activation of SIRT3 could mediate hippocampal synaptic adaptations and ameliorate cognitive deficits in APP mutant mice. [ 25 ] Moreover, SIRT3 deficiency could induce brain mitochondrial dysfunction, microgliosis and elevate NLRP3 inflammasomes and IL‐1β expression, which exacerbated cognitive decline in calorie‐rich western diet induced mice. [ 26 ] Meanwhile, SIRT3‐mediated deacetylation of mitochondrial SOD2 was necessary to prolong mitochondrial NLRP3 inflammasome assembly, decreasing NLRP3 super complex formation and activation.…”

Studying the Relationship of Intermittent Fasting and β-Amyloid in Animal Model of Alzheimer’s Disease: A Scoping Review

“…One study incorporated 5xFAD mice that carry five familial AD mutations: Swedish (K670N), M671L), Florida (1716V), and London (V7171) mutations in human amyloid precursor protein (APP695) and two mutations (M146L and L286V) in the human presenilin 1 protein [ 38 ]. One study employed a triple transgenic AD mice model with one harboring Swedish double mutation, beta-amyloid precursor protein (betaAPPSwe), presenilin-1 (PS1M146V), and human tauP301L [ 42 ], while the other was an APP knock-in mice (APP NL-G-F ) that developed several features of AD [ 39 ]. Furthermore, one other study employed a double transgenic APP-PS1 mouse [ 41 ].…”

“…The age of the mice and rats at the start of the intervention varied from study to study. Three studies started the intervention as early as two to three months old [ 38 , 40 , 42 ], while the other at five months old [ 41 ], and lastly at 12 months old [ 39 ].…”

“…Three studies underwent the ADF method where food was deprived for a period of 24 h [ 38 , 41 , 42 ], while the remaining two studies employed a TRF protocol of 3 h per day [ 40 ] and 2 days per week of food deprivation [ 39 ]. The intervention duration was also found to be wide-ranging across studies.…”

“…For the ADF protocol, the shortest duration was 4 months [ 38 ], followed by 5 months [ 41 ], and the longest at 14 months [ 42 ]. The time-restricted protocol of 3 h per day started at the beginning of the dark cycle (7 to 10 PM), which corresponds to the morning for humans for a period of 2 months [ 40 ], while the 2 days per week food restriction was conducted for 9 months [ 39 ].…”