Neuronal ?-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer's disease

Presenilin mutations that alter ?-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether ?-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of ?-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic ?-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to ?-secretase inhibition. Thus, ?-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of ?-secretase impairs synapses by lowering cholesterol levels. Overall design: Differential gene expression analysis of bulk RNA-seq data for human iN cells (generated by Ngn2 overexpression) and mouse glia treated with the gamma-secretase inhibitors DAPT (40 µM) or LY411575 (2.5 µM), relative to DMSO-treated controls (0.5%).