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

Abstract

The accumulation of amyloid protein A{beta} 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 {varepsilon}4 allele of Apolipoprotein E (ApoE4), which potentiates pre-symptomatic endosomal dysfunction and defective clearance of A{beta}, 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 A{beta} 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 NHE6KO mouse model shows elevated A{beta} 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.