Dataset Information

?-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer's disease pathology.

ABSTRACT: Alzheimer's disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism. One of the ketone bodies produced as a result of ketogenesis, ?-hydroxybutyrate (BHB), is known to inhibit NLRP3 inflammasome activation. Therefore, we tested if BHB inhibition of the NLRP3 inflammasome reduces overall AD pathology in the 5XFAD mouse model of AD. Here, we find BHB levels are lower in red blood cells and brain parenchyma of AD patients when compared with non-AD controls. Furthermore, exogenous BHB administration reduced plaque formation, microgliosis, apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) speck formation, and caspase-1 activation in the 5XFAD mouse model of AD. Taken together, our findings demonstrate that BHB reduces AD pathology by inhibiting NLRP3 inflammasome activation. Additionally, our data suggest dietary or pharmacological approaches to increase BHB levels as promising therapeutic strategies for AD.

SUBMITTER: Shippy DC

PROVIDER: S-EPMC7507727 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer's disease pathology.

Shippy Daniel C DC Wilhelm Connor C Viharkumar Patel A PA Raife Thomas J TJ Ulland Tyler K TK

Journal of neuroinflammation 20200921 1

Alzheimer's disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism. One of the ketone bodies produced as a result of ketogenesis, β-hydroxybutyrate (BHB), is known to inhibit NLRP3 inflammasome activation. Therefore, we tested if BHB inhibition of the NLRP3 i ...[more]

PMID: 32958021

Similar Datasets

Project description:BackgroundAlzheimer's disease (AD) is the most prevalent neurodegenerative disorder leading to cognitive impairment in the elderly, and no effective treatment exists. Increasing evidence has demonstrated that physical therapy and electroacupuncture (EA) effectively improve spatial learning and memory abilities. Nevertheless, the mechanism underlying the effects of EA on AD pathology is largely unexplored. Acupuncture at Zusanli (ST 36) has previously been shown to improve cognitive impairment in AD, but the mechanism is unclear. According to recent studies, EA drives the vagal-adrenal axis from the hindlimb ST 36 acupoint but not from the abdominal Tianshu (ST 25) to curb severe inflammation in mice. This study examined whether ST 36 acupuncture improves cognitive dysfunction in AD model mice by improving neuroinflammation and its underlying mechanism.MethodsMale 5xFAD mice (aged 3, 6, and 9 months) were used as the AD animal model and were randomly divided into three groups: the AD model group (AD group), the electroacupuncture at ST 36 acupoint group (EA-ST 36 group), and the electroacupuncture at ST 25 acupoint group (EA-ST 25 group). Age-matched wild-type mice were used as the normal control (WT) group. EA (10 Hz, 0.5 mA) was applied to the acupoints on both sides for 15 min, 5 times per week for 4 weeks. Motor ability and cognitive ability were assessed by the open field test, the novel object recognition task, and the Morris water maze test. Thioflavin S staining and immunofluorescence were used to mark Aβ plaques and microglia. The levels of NLRP3, caspase-1, ASC, interleukin (IL)-1β, and IL-18 in the hippocampus were assayed by Western blotting or qRT-PCR.ResultsEA at ST 36, but not ST 25, significantly improved motor function and cognitive ability and reduced both Aβ deposition and microglia and NLRP3 inflammasome activation in 5×FAD mice.ConclusionEA stimulation at ST 36 effectively improved memory impairment in 5×FAD mice by a mechanism that regulated microglia activation and alleviated neuroinflammation by inhibiting the NLRP3 inflammatory response in the hippocampus. This study shows that ST 36 may be a specific acupoint to improve the condition of AD patients.

Dataset Information

?-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer's disease pathology.

Publications

β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer's disease pathology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets