2021/08/12 by Hao Wang, Joshua A. Kulas, Chao Wang +3 · 1 citation
Medicine · Biochemistry, Genetics and Molecular Biology · Neuroscience · #Alzheimer's disease research and treatments #Lipid Membrane Structure and Behavior #Neuroscience and Neuropharmacology Research #Endogeny #Astrocyte #Context (archaeology) #Neuroscience #Mechanism (biology) #Pathogenesis #Alzheimer's disease #Amyloid precursor protein #Amyloid (mycology) #Neurodegeneration #Disease #Cholesterol synthesis #Cholesterol #Apolipoprotein E #Biology #Central nervous system #Medicine #Endocrinology #Internal medicine #Biochemistry #Immunology
paper · pdf · doi:10.1073/pnas.2102191118
openalex publication_date 2021/08/12 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
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.