Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH

Significance Alzheimer’s disease is the most common cause of dementia in the elderly. Most cases occur sporadically, with 40–65% of patients carrying at least one copy of the E4 allele of Apolipoprotein E. Because no drug exists that can halt disease progress, there is strong interest in understanding the presymptomatic role of endosomes. We show that excessive endosomal acidification in ApoE4 astrocytes is caused by downregulation of the Na + /H + exchanger NHE6 and results in defective clearance of amyloid beta (Aβ) peptide by intracellular sequestration of the LRP1 receptor. Epigenetic modifiers restore NHE6 expression to alkalinize endosomal pH, increase surface expression of LRP1, and correct Aβ clearance in astrocytes. Thus, endosomal pH emerges as a target for the correction of amyloid disorders.