The Amyloid Clearance Defect in ApoE4 Astrocytes is Corrected by Epigenetic Restoration of NHE6

Summary The accumulation of amyloid protein Aβ in senile plaques is a key driver and hallmark of Alzheimer disease (AD), a major cause of death and dementia in the elderly. The strongest genetic risk factor in sporadic AD is the ε4 allele of Apolipoprotein E (ApoE4), which potentiates pre-symptomatic endosomal dysfunction and defective clearance of Aβ, although how these two pathways are linked has been unclear. Here, we show that aberrant accumulation of endosomal protons in ApoE4 astrocytes traps the LRP1 receptor in non-productive intracellular compartments, leading to loss of surface expression and Aβ clearance. Hyperacidification of endosomal pH is caused by selective down regulation of the Na + /H + exchanger NHE6, which functions as a critical proton leak pathway, in ApoE4 brain and astrocytes. In vivo , the NHE6 KO mouse model shows elevated Aβ in the brain. Epigenetic restoration of NHE6 expression with histone deacetylase inhibitors normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking and amyloid clearance. Thus, NHE6 is a prominent effector of ApoE4 and emerges as a promising therapeutic target in Alzheimer disease.