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!
BDNF (158 posts to August 2013)
Acetoacetate Improves Memory in Alzheimer’s Mice via Promoting Brain-Derived Neurotrophic Factor and Inhibiting Inflammation
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.
No comments:
Post a Comment