A ketogenic diet improves motor performance but does not affect β-amyloid levels in a mouse model of Alzheimer's Disease

Abstract

β-Amyloid (Aβ), a small, fibrillogenic peptide, is known to play an important role in the pathogenesis of Alzheimer’s disease (AD) in the brain. In addition, Aβ accumulates in skeletal muscle cells in individuals with sporadic inclusion body myositis (sIBM), an age-related muscle disease. Because of the socioeconomic burden associated with age-related diseases, particularly AD, there has been considerable emphasis on studying potential therapeutic strategies. The high fat, low carbohydrate ketogenic diet has been used extensively to treat refractory childhood epilepsy and has been studied as a potential treatment for other neurological diseases, including Parkinson’s disease and AD. In this study, we fed young APP/PS1 knock-in mice, which have a whole body knock-in of AD-related genes, a ketogenic diet and determined the effect on Aβ levels in the brain and skeletal muscle, as well motor performance and oxidative stress. Aβ and its precursor, the β-C-terminal fragment of amyloid precursor protein (CTFβ), were unchanged overall in both the brain and quadriceps after 1 month on the ketogenic diet, and there was no effect on nitrotyrosine, a product of oxidative stress. The ketogenic diet improved performance on the Rota-rod apparatus (p=0.007), however. These data indicate that the ketogenic diet may have some efficacy in the treatment of both neurologic and muscle diseases though the underlying mechanisms do not involve amelioration of Aβ pathology.

Ketosis as a treatment for multiple metabolic and neurodegenerative pathologies

“…Other studies showed similar results; KD improved rotarod performance in young (1-2 month) nontransgenic and APP+PS1 mice when fed KD for one month [69], while no effects on the soluble amyloid in the brain or muscle could be detected by ELISA, similarly to the previous study [66].…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…However, patient compliance on ketogenic diets is challenging owing to its high fat and low carbohydrate content. In addition, there are studies indicating that ketone bodies have little effect on AD pathology, despite benefits on motor performance [57,66]. Two early proof-of-concept clinical studies, investigating ketone bodies for mild-to-moderate AD, reported significant improvements on multiple measures of cognition [58,59].…”

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“…This is based on studies with victims of severe brain injury or mouse models. The latter show that ketogenic diets impact the tau protein associated with Alzheimer's disease plaques, in some but not all studies, and improve motor activity, but not cognition (17,18,35,36). Such studies also show that excess calorie intake or high-CHO diets impair not only the formation of brain-derived neurotrophic factor, but also its signaling in the hippocampus, which is critical for memory (37).…”