Fig. 5. Loss of NHE6 function is central to the endosomal pathology in Alzheimer’s disease.

NHE6 blocks BACE1-mediated amyloid production and promotes LRP1-mediated Aβ clearance. Downregulation of NHE6 expression or activity contributes to the endosomal pathology observed in pre-symptomatic AD brains by causing over-acidification of early and recycling endosomes, which creates an imbalance between Aβ production and clearance pathways, culminating in Aβ plaques, neurodegeneration, and dementia. Depiction of dementia is adapted from the self-portrait of Mr. William Utermohlen, an artist and AD patient. APP amyloid precursor protein, BACE1 β-secretase, GSC gamma secretase complex, LRP1 LDL receptor-related protein 1, Aβ amyloid β