Neuroprotective function of astrocyte p75 ^NTR in Alzheimer’s Disease through regulation of cholesterol metabolism

Reactive astrogliosis in Alzheimer’s Disease (AD) involves profound changes in the morphology, metabolism and secretion profile of astrocytes, but whether astrogliosis is beneficial or harmful, and under which conditions, remain open questions. Here we report an unexpected neuroprotective function of death receptor p75 ^NTR in astrocytes through its ability to regulate cholesterol metabolism. AD knock-in mice expressing signaling-deficient p75 ^NTR variants in astrocytes showed enhanced Aβ burden, brain histopathology and cognitive impairment, even when variants were introduced late in the disease process. Astrocytes expressing dysfunctional p75 ^NTR variants showed impaired uptake of Aβ oligomers, and their conditioned medium enhanced Aβ production in AD neurons. p75 ^NTR signaling negatively regulated astrocyte cholesterol biosynthesis and secretion, while cholesterol depletion restored Aβ uptake in mutant astrocytes and reduced Aβ production in AD neurons. In agreement with the role of astrocyte-derived cholesterol, statin treatment reverted the effects of astrocyte p75 ^NTR mutants on AD neuropathology. Thus, although neuronal p75 ^NTR has been widely recognized to amplify AD, astrocyte p75 ^NTR plays a neuroprotective role.