SIRT1 Overexpression in Mouse Hippocampus Induces Cognitive Enhancement Through Proteostatic and Neurotrophic Mechanisms

Abstract

SIRT1 induces cell survival and has shown neuroprotection against amyloid and tau pathologies in Alzheimer's disease (AD). However, protective effects against memory loss or the enhancement of cognitive functions have not yet been proven. We aimed to investigate the benefits induced by SIRT1 overexpression in the hippocampus of the AD mouse model 3xTg-AD and in control non-transgenic mice. A lentiviral vector encoding mouse SIRT1 or GFP, selectively transducing neurons, was injected into the dorsal CA1 hippocampal area of 4-month-old mice. Six-month overexpression of SIRT1 fully preserved learning and memory in 10-month-old 3xTg-AD mice. Remarkably, SIRT1 also induced cognitive enhancement in healthy non-transgenic mice. Neuron cultures of 3xTg-AD mice, which show traits of AD-like pathology, and neuron cultures from non-transgenic mice were also transduced with lentiviral vectors to analyze beneficial SIRT1 mechanisms. We uncovered novel pathways of SIRT1 neuroprotection through enhancement of cell proteostatic mechanisms and activation of neurotrophic factors not previously reported such as GDNF, present in both AD-like and healthy neurons. Therefore, SIRT1 may increase neuron function and resilience against AD.

Melatonin induces mechanisms of brain resilience against neurodegeneration

“…This study assessed the beneficial effects of melatonin treatment on cognition and brain status in NoTg and 3xTg‐AD mice. 3xTg‐AD mice presented impairment of recognition memory evaluated by the NOR test as previously reported . Observations also indicated deterioration in exploratory behavior and increase in anxiety‐like conduct, comprising the BPSD‐like phenotype characteristic of 3xTg‐AD strain .…”

“…Male adult 3xTg‐AD mice strain harboring familial AD mutations PS1/M146V, APPswe, and tauP301L were used in this study. These mice mimic many of the critical hallmarks of AD such as amyloid and tau pathologies, impaired learning and memory, presence of behavioral and psychological symptoms of dementia (BPSD)‐like, and oxidative stress . Furthermore, 3xTg‐AD mice reproduce the temporal course and areas affected by amyloid and tau pathology of AD neuropathology .…”

“…The latency of entry into the lit compartment, the time spent in the lit compartment, and the horizontal activity (crossings) and vertical activity (rearings) were recorded. The novel object recognition (NOR) test was used to evaluate learning and memory through circuits that integrate hippocampus and cortical abilities by considering the tendency of rodents to spend more time exploring a novel object than a familiar one . Object exploration was defined as the orientation of the nose to the object at less than 2 cm.…”

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

“…The novel object recognition (NOR) test was performed from 11:00 am to 3:00 pm Exploration time was recorded for the discrimination index calculation, and the discrimination index was calculated as [novel ( t ) − familiar ( t )]/[total time ( t ) at novel + familiar]. On the 2nd day after TMT exposure, the exploration times of the mice were recorded and then recorded again after 2 hours.…”

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders

“…SIRT1also removes acetyl groups from tau, thus relieving the p300-mediated inhibition of phospho-tau degradation [148]. Manipulations of sirtuin activity could therefore influence tau, potentially changing the number of neurofibrillary tangles (NFT) [149, 150]. Moreover, SIRT1 and tau share common upstream regulation mechanism, as both are targets of microRNA-132 [151] and of ademosine monophosphate-activated kinase (AMPK, which leads to the inhibition of the crucial tau kinase GSK-3β, and modulates SIRT1 signaling in a complex manner) [152–154].…”