Presynaptic membrane cholesterol homeostasis: A multifactorial contender in Alzheimer’s disease pathogenesis

Abstract

AbstractBackgroundCholesterol (Chol) is highly enriched in the axonal plasma membrane and crucial for exo‐/endocytosis of synaptic vesicles (SVs). At axon terminals, the neuronal activity causes massive SV turnover and in turn perturbs Chol homeostasis between the surface and intracellular membranes. Amyloid precursor protein (APP), enriched at axon terminals, exhibits an intricate association with Cholesterol in multiple aspects. First, it directly binds to Chol via a Chol‐binding motif (CBM) that overlaps with the Abeta sequence. Second, its cleavage by secretases is heavily influenced by Chol. Third, its cleavage products, namely AICD, regulates neurons’ Chol uptake. Our recent work revealed an even more intriguing relationship between APP and neuronal membrane Chol, an inverse correlation between the two in the synaptic membrane.MethodHere, we developed a novel fluorescent reporter for acute surface‐intracellular exchange of Chol at active synapses.ResultSurprisingly, we observed a significantly delayed Chol recycling upon stimulation, which intriguingly coordinates with APP turnover at axon terminals. Moreover, point mutations disrupting APP‐Chol binding disengaged the APP and Chol coordination, and disrupted Chol recycling as well as surface Chol distribution. Such disruption led to disruption in SV regeneration, presynaptic sustainability, and axon membrane integrity after extended stimulation or moderate reduction of membrane Chol. Moreover, familial Alzheimer’s Disease (AD) mutations outside of APP’s Chol‐binding motif but increasing APP surface distribution also altered Chol recycling and distressed axon functionality as well as integrity. Last but not the least, we found AD‐related pathological phenotypes like hyperphosphorylated Tau and gliosis as well as higher death rate in aging APP knockout mice.ConclusionTaking together, we postulate that APP and its proteolytic processing a part of the regulatory mechanism for the homeostasis of neuronal membrane cholesterol. More importantly, presynaptic Chol dysregulation is a multifactorial contender in AD pathogenesis.