Endosomal Acidification by NHE6-depletion Corrects ApoE4-mediated Synaptic Impairments and Reduces Amyloid Plaque Load

Apolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimers disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger NHE6 restores vesicular trafficking and normalizes synaptic homeostasis. Using NHE6 conditional KO mice we now also show that disruption of NHE6 activates the resident microglia and thus reduces early and advanced amyloid plaque formation in humanized APPNL-F knockin mice in the presence or absence of ApoE4 by approximately 80%. These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4 induced endolysosomal trafficking defect, while at the same time shifting the resident microglia from the dormant, homeostatic to the damage-associated, activated state.