Ketogenic diet ameliorates cognitive impairment and neuroinflammation in a mouse model of Alzheimer’s disease

Xu, Yunlong; Jiang, Chenchen; Wu, Junyan; Liu, Peidong; Deng, Xiaofei; Zhang, Yadong; Peng, Bo; Zhu, Ying‐Jie

doi:10.1111/cns.13779

Cited by 55 publications

(58 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ED suppression can be attained with similar effect size and electrophysiological profile by small molecule ketone ester compounds that provide ketone bodies pharmacologically. These data provide a mechanistic understanding of earlier observations of visuo-spatial memory improvement with KD (Xu et al , 2022; Yin et al, 2016) or a ketone ester diet (Kashiwaya et al , 2013) in AD models. We are the first to show that KD reduces AD-induced epileptiform activity, providing a functional mechanism of action linked to rapid cognitive decline in AD patients (Lam et al, 2017; Vossel et al, 2013; Vossel et al, 2016) and with translational applicability in patients (Bakker et al, 2015; Bakker et al, 2012; Vossel et al, 2021; Vossel et al, 2017).…”

Section: Discussionsupporting

confidence: 62%

“…Reports of the effect of KD or ketone bodies on Aβ deposition have been conflicting, with Aβ either reduced (Kashiwaya et al , 2013; Van der Auwera et al, 2005; Xu et al, 2022) or unchanged (Aso et al, 2013; Beckett et al, 2013; Brownlow et al, 2013). While changes in plaque accumulation could not explain the very rapid kinetics we observed for the effect of KD and ketone esters on epileptiform activity, we nevertheless carried out an exploratory immunohistochemical analysis of mice after 7 months on KD (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Small-molecule ketone esters treat brain network abnormalities in an Alzheimer’s disease mouse model

Newman

Kroll

et al. 2022

Preprint

View full text Add to dashboard Cite

Altered brain network activity and the resulting hypersynchrony are important for the pathogenesis of cognitive decline in Alzheimer's disease (AD) mouse models. Treatments that reduce epileptiform discharges (EDs) or network hyperactivity improve cognition in AD models and humans. We first show that ketogenic diet, but not fasting, rapidly and persistently reduced EDs in the hAPPJ20 Alzheimer's mouse model over timescales of hours to months. Then, to identify the specific mechanism of the pleiotropic ketogenic diet, we developed small molecule ketone esters to deliver ketone bodies pharmacologically. Two ketone esters recapitulate ED suppression without other dietary manipulation, over time scales of minutes to one week. This small molecule rescue was associated with reduced low-frequency oscillatory activity similar to the recently reported mechanism of an NMDA receptor modulator molecule in this model. Long-term KD resulted in cognitive improvement and in a sex-stratified analysis also improved survival in the more severely affected hAPPJ20 males. Agents that deliver ketone bodies via small molecules or act on downstream targets may hold therapeutic promise in AD through the mechanism of improved network function and reduced epileptiform activity.

show abstract

Section: Discussionsupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Small-molecule ketone esters treat brain network abnormalities in an Alzheimer’s disease mouse model

Newman

Kroll

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Compared to a standard chow diet, APP/V717I transgenic mice fed a 43-day KD had a 25% reduction in brain Aβ levels ( Van der Auwera et al, 2005 ). Similarly, 5xFAD mice fed a 4-month KD had reduced hippocampal Aβ deposition compared to the standard chow diet ( Xu et al, 2021 ). Contrary to these findings, studies of a 16-week ( Brownlow et al, 2013 ) and 1-month ( Beckett et al, 2013 ) KD in APP/PS1 transgenic mice demonstrated improvements in motor function but not Aβ deposition; however, the APP/PS1 mice on the 1-month KD had decreases in brain and skeletal muscle CTF99 ( Beckett et al, 2013 ), the precursor for Aβ.…”

Section: Ketotherapies and Amyloid-βmentioning

confidence: 99%

“…Of note, elevations of Aβ have also been shown to stimulate pro-inflammatory cytokine expression by microglia, which may be more prominent in early stages of pathology while Aβ oligomers are still soluble rather than deposited into fibrillar plaques ( White et al, 2005 ; Sondag et al, 2009 ). The KD has also been shown to decrease inflammatory microgliosis in several models including the 5xFAD mouse model ( Xu et al, 2021 ).…”

Section: Ketotherapies and Amyloid-βmentioning

confidence: 99%

Potential for Ketotherapies as Amyloid-Regulating Treatment in Individuals at Risk for Alzheimer’s Disease

et al. 2022

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a progressive neurodegenerative condition characterized by clinical decline in memory and other cognitive functions. A classic AD neuropathological hallmark includes the accumulation of amyloid-β (Aβ) plaques, which may precede onset of clinical symptoms by over a decade. Efforts to prevent or treat AD frequently emphasize decreasing Aβ through various mechanisms, but such approaches have yet to establish compelling interventions. It is still not understood exactly why Aβ accumulates in AD, but it is hypothesized that Aβ and other downstream pathological events are a result of impaired bioenergetics, which can also manifest prior to cognitive decline. Evidence suggests that individuals with AD and at high risk for AD have functional brain ketone metabolism and ketotherapies (KTs), dietary approaches that produce ketone bodies for energy metabolism, may affect AD pathology by targeting impaired brain bioenergetics. Cognitively normal individuals with elevated brain Aβ, deemed “preclinical AD,” and older adults with peripheral metabolic impairments are ideal candidates to test whether KTs modulate AD biology as they have impaired mitochondrial function, perturbed brain glucose metabolism, and elevated risk for rapid Aβ accumulation and symptomatic AD. Here, we discuss the link between brain bioenergetics and Aβ, as well as the potential for KTs to influence AD risk and progression.

show abstract

“…In a recent study, a ketogenic dietary intake for 4 months improved spatial and working memory and decreased amyloid plaque deposition and microglia activation in the AD mouse model 5XFAD [67]. Similarly, KD feeding for 1 month in APP/PS1 knock-in mice ameliorated their reduced motor performance, but their beta amyloid levels were unchanged in both brain and muscle [68].…”

Section: Nervous Systemmentioning

confidence: 93%

Molecular Mechanisms Underlying the Bioactive Properties of a Ketogenic Diet

Murakami

Tognini

2022

Nutrients

View full text Add to dashboard Cite

The consumption of a high-fat, low-carbohydrate diet (ketogenic diet) has diverse effects on health and is expected to have therapeutic value in neurological disorders, metabolic syndrome, and cancer. Recent studies have shown that a ketogenic diet not only pronouncedly shifts the cellular metabolism to pseudo-starvation, but also exerts a variety of physiological functions on various organs through metabolites that act as energy substrates, signaling molecules, and epigenetic modifiers. In this review, we highlight the latest findings on the molecular mechanisms of a ketogenic diet and speculate on the significance of these functions in the context of the epigenome and microbiome. Unraveling the molecular basis of the bioactive effects of a ketogenic diet should provide solid evidence for its clinical application in a variety of diseases including cancer.

show abstract

Ketogenic diet ameliorates cognitive impairment and neuroinflammation in a mouse model of Alzheimer’s disease

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 55 publications

References 61 publications

Small-molecule ketone esters treat brain network abnormalities in an Alzheimer’s disease mouse model

Small-molecule ketone esters treat brain network abnormalities in an Alzheimer’s disease mouse model

Potential for Ketotherapies as Amyloid-Regulating Treatment in Individuals at Risk for Alzheimer’s Disease

Molecular Mechanisms Underlying the Bioactive Properties of a Ketogenic Diet

Contact Info

Product

Resources

About