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, β-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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and impaired cognitive functions
We demonstrate that exogenous BHB administration to mice carrying human presenilin 1 (PSEN1) and amyloid precursor protein (APP) with 5 familial AD mutations under the CD90 promoter, which deposit Aβ plaques [23] (5XFAD mice), decreases overall AD pathology through inhibition of the inflammasome
We found that BHB levels were significantly reduced in the brain tissue of AD patients when compared with non-AD controls (P = 0.0036; two-tailed Student’s t test] (Fig. 1b, d) with a strong correlation between BHB levels in the brain and red blood cells (Fig. 1e)
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and impaired cognitive functions. Recent evidence suggests age-related metabolic dysfunction plays a role in promoting cognitive impairment and overall AD pathology [1,2,3,4,5]. In response to Aβ aggregation, microglia promote Aβ and tau clearance and create physical barriers to protect neurons from neurotoxic plaque, and drive neuroinflammation that damages neurons [7,8,9,10,11,12]. Chronic activation of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome has emerged as an important mechanism in continual neuroinflammation that significantly increases AD pathology [13]. Inhibiting NLRP3 activation could be a promising therapeutic strategy for AD
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