[220204 Àú³Î¹ßÇ¥] Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol ±èÁöÀº ¦¢ 2022-02-03 HIT 44162 |
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SignificanceThe accumulation of amyloid ¥â (A¥â) in the brain appears to be a necessary event in the pathogenesis of Alzheimer¡¯s disease (AD). However, processes linked to the endogenous regulation of A¥â production are still not completely understood. Here, the authors show that A¥â accumulation in neurons is tightly regulated by cholesterol synthesis and apoE transport from astrocytes. The study provides a molecular context for understanding the endogenous regulation of A¥â accumulation and why it correlates with AD. The tight regulation suggests that A¥â may perform an important cellular function. A complete understanding of the mechanism is likely necessary to predict whether the selective removal of A¥â has potential for a therapeutic benefit. AbstractAlzheimer¡¯s disease (AD) is characterized by the presence of amyloid ¥â (A¥â) 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 A¥â 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 ¥â- and ¥ã-secretases to generate A¥â-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 ¥á-secretase and gives rise to soluble APP-¥á (sAPP-¥á), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on ¥á-, ¥â-, and ¥ã-secretase trafficking, suggesting that the ratio of A¥â to sAPP-¥á is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits A¥â accumulation and enables the astrocyte regulation of A¥â accumulation by cholesterol signaling. |
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