Acetoacetate Improves Memory in Alzheimer’s Mice via Promoting Brain-Derived Neurotrophic Factor and Inhibiting Inflammation

 Since BDNF  is good for our stroke rehabilitation, WHOM is going to do the human testing on this to see if it helps stroke recovery? With NO stroke leadership, NOTHING EVER OCCURS!

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Acetoacetate Improves Memory in Alzheimer’s Mice via Promoting Brain-Derived Neurotrophic Factor and Inhibiting Inflammation

Xiao-Jun Wu, MD, PhD https://orcid.org/0000-0002-3809-6832, Qin-Qin Shu, […], and Bin Hao, MD, PhD https://orcid.org/0000-0003-4206-5374 haobin@shca.org.cn+2View all authors and affiliations

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https://doi.org/10.1177/15333175221124949

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Abstract

The ketone bodies, especially the β-hydroxybutyrate, had been shown to modulate the function of the central nervous system and prevent the pathological progression of Alzheimer’s disease (AD). However, little is known about the role of acetoacetate in the AD brain. Thus, we intraventricularly injected acetoacetate into familial AD mice (APPSWE) for 14 days and monitored their memory and biochemical changes. During the behavior test, acetoacetate at 100 mg/kg led to significant improvement in both Y-maze and novel object recognition tests (NORTs) (both P < .05), indicating ameliorating spatial and recognition memory, respectively. Biomedical tests revealed two mechanisms were involved. Firstly, acetoacetate inhibited the GPR43-pERK pathway, which led to apparent inhibition in tumor necrosis factor-α and Interleukin-6 expression in the hippocampus in a concentration-dependent manner. Secondarily, acetoacetate stimulated the expression of hippocampal brain-derived neurotrophic factor (BDNF). We concluded that acetoacetate could ameliorate AD symptoms and exhibited promising features as a therapeutic for AD.

Introduction

Neurodegenerative diseases, such as Alzheimer’s disease (AD), have become the one major contributor to cognition impairment and dramatically affect life quality.¹ AD is characterized by pathological accumulation of amyloid-beta (Aβ) protein and the formation of intracellular neurofibrillary tangles, which initiates a cascade of neuroinflammation and leads to neuronal death and a decline in memory and learning behaviors.² Since AD is currently considered to be uncurable, addressing modifiable risk factors to prevent AD remains the most promising strategy. In this regard, increasing evidence suggests that daily diet could play a significant role in preventing and slowing AD’s pathological changes.¹

Emerging evidence suggested that the AD brain had impaired glucose metabolism.³ Previous studies demonstrated that cerebral glucose metabolism is reduced by 20-40% in AD⁴, especially in the hippocampus regions.⁵ Although fat is the optimal alternative to glucose, the brain cannot utilize fatty acids. Ketone bodies feature water-soluble and lower molecular weight, which enable them to efficiently cross the blood-brain barrier.⁶ Based on these results, literature had shown that ketone has become the major alternative energy substrate for neurons in the AD brain.^7-9 Interestingly, emerging data indicates ketones are not only merely nutritional molecules but have potentially positive effects on AD as well. Previously, the β-HB has been shown to improve AD symptoms and prevent AD’s pathological progression.^8,10,11 Acetoacetate is the central ketone body as β-HB is generated from acetoacetate by the β-HB dehydrogenase.¹² Additionally, ketones are transported into cells at different rates, with the uptake of acetoacetate being twice that of β-HB at a given arterial concentration.¹³ However these features, little is known about the role of acetoacetate on the pathological progression of AD.

GPR43, also known as free fatty acid receptor 2 (FFAR2), is a dual-coupling G protein-coupled receptor (GPCR) that binds with both the pertussis toxin-sensitive Gq and Gi/o proteins.¹⁴ Previously, the GPR43 is identified as a cognate receptor for short-chain fatty acids (SCFA).¹⁵ The SCFAs are microbial metabolites in the intestine, which elicit a plethora of effects on systemic health, including modulating the microbiota-gut-brain axis¹⁶ and the inflammation process.¹⁷ Thus, as the receptor of SCFAs, the GPR43 has been suggested to be also responsible for the diverse regulatory and therapeutic effects across a spectrum of diseases. GPR43 is abundantly expressed in immune cells¹⁵ and modulates inflammatory response.¹⁸ Since inflammation has been strongly implicated in the pathogenesis of AD,¹⁹ the GPR43 has become an appealing pharmaceutical target with therapeutic applications for AD. Recently, GPR43 has been identified as a specific receptor for acetoacetate.²⁰ Additionally, GPR43 expression has been newly discovered in the brain, especially in the hippocampus.²¹ However, basic unanswered questions persist about the involvement of GPR43, as well as its ligand acetoacetate, in preventing the pathological progression of AD.

In the current study, we explore the effects and underlying mechanisms of exogenous acetoacetate on mice with memory disorders. By using the intra-ventricular injection method, we tested the hypothesis that elevation of acetoacetate in the central nervous system (CNS) could improve the memory of AD mice.