Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models

Area of Science:

• Neuroscience
• Gerontology
• Metabolic research

Background:

• Fasting-mimicking diet (FMD) cycles are known to reduce aging and disease risk factors.
• Alzheimer's disease (AD) is a progressive neurodegenerative disorder with significant unmet medical needs.
• The potential impact of FMD on AD pathology and cognitive function requires investigation.

Purpose of the Study:

• To investigate the efficacy of FMD cycles in ameliorating cognitive decline and AD pathology in established mouse models of Alzheimer's disease.
• To compare the effects of FMD with protein restriction (PR) in AD mouse models.
• To explore the underlying mechanisms, including neuroinflammation and oxidative stress, by which FMD may exert its effects.

Main Methods:

• E4FAD and 3xTg AD mouse models were subjected to cycles of FMD or protein restriction.
• Cognitive function was assessed using behavioral tests.
• Brain tissue was analyzed for Alzheimer's disease hallmarks such as amyloid-beta (Aβ) plaque load and hyperphosphorylated tau.
• Neurogenesis, microglia activation, and the expression of neuroinflammatory genes, including NADPH oxidase (Nox2), were evaluated.
• Studies included genetically modified mice lacking Nox2 and treatment with an NADPH oxidase inhibitor (apocynin).
• Feasibility and safety of FMD were assessed in a small cohort of human AD patients.

Main Results:

• FMD cycles significantly reduced cognitive decline and AD pathology in both E4FAD and 3xTg mouse models, outperforming protein restriction.
• In 3xTg mice, long-term FMD decreased hippocampal Aβ load, reduced hyperphosphorylated tau, enhanced neural stem cell genesis, decreased microglia numbers, and lowered expression of neuroinflammatory genes like Nox2.
• Mice lacking Nox2 or treated with apocynin exhibited improved cognition and reduced microglia activation compared to controls.
• Clinical data suggested FMD cycles are feasible and generally safe in a small group of AD patients.

Conclusions:

• FMD cycles demonstrate a potent ability to delay cognitive decline and mitigate AD pathology in preclinical models.
• The beneficial effects of FMD in AD appear to be mediated, at least in part, by the reduction of neuroinflammation and/or superoxide production.
• FMD represents a promising non-pharmacological intervention strategy for Alzheimer's disease, warranting further clinical investigation.