Neuroprotective function of astrocyte p75NTR 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 p75NTR in astrocytes through its ability to regulate cholesterol metabolism. AD knock-in mice expressing signaling-deficient p75NTR variants in astrocytes showed enhanced Abeta burden, brain histopathology and cognitive impairment, even when variants were introduced late in the disease process. Astrocytes expressing dysfunctional p75NTR variants showed impaired uptake of Abeta oligomers, and their conditioned medium enhanced Abeta production in AD neurons. p75NTR signaling negatively regulated astrocyte cholesterol biosynthesis and secretion, while cholesterol depletion restored Abeta uptake in mutant astrocytes and reduced Abeta production in AD neurons. In agreement with the role of astrocyte-derived cholesterol, statin treatment reverted the effects of astrocyte p75NTR mutants on AD neuropathology. Thus, although neuronal p75NTR has been widely recognized to amplify AD, astrocyte p75NTR plays a neuroprotective role.