Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Abstract

Alzheimer’s disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβ-peptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α (sAPP-α), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting that the ratio of Aβ to sAPP-α is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits Aβ accumulation and enables the astrocyte regulation of Aβ accumulation by cholesterol signaling.

Blocking cholesterol storage to treat Alzheimer’s disease

“…Given the strong genetic association between LOAD and lipid metabolism, LOAD can be considered a unique lipid disease. Recent evidence from several laboratories supports this concept [ 20 – 22 ].…”

Phytosterols: Potential Metabolic Modulators in Neurodegenerative Diseases

“…Reports have suggested the role of cholesterol in amyloid precursor protein (APP) processing [40,[51][52][53]; thus, cholesterol may be considered as a target for developing drugs to treat AD. Phytosterols are structurally similar to cholesterol and have been widely used to reduce blood cholesterol [54].…”

Sirtuins as Potential Therapeutic Targets for Mitigating Neuroinflammation Associated With Alzheimer’s Disease

“…The accumulation of cholesterol in neurons promotes the interaction of APP with β- and γ-secretases in lipid clusters (lipid rafts) in neuronal membrane, resulting in Aβ formation ( Di Paolo and Kim, 2011 ). It was recently shown that cholesterol and apolipoprotein E (apoE) derived from astrocytes play an important role in amyloid plaque deposition through the regulation of membrane lipid raft function ( Wang et al, 2021 ). Moreover, genetic variation in apoE, a cholesterol transport protein is identified as a risk factor for late-onset AD ( Corder et al, 1993 ).…”