The Na+/H+ Exchanger NHE6 Links Endosomal pH to Amyloid Pathologies in Alzheimer's Disease

Abstract

Endosomal dysfunction has been implicated as an early step in neurodegeneration. Endosomes are a major site of production of Aβ peptide from the processing of amyloid precursor protein (APP) by clipping enzymes (β and γ-secretases). The β-secretase enzyme BACE-1 requires acidic lumen pH for optimum function and acid pH promotes Aβ aggregation. The endosomal Na+/H+ exchanger NHE6 provides a leak pathway for protons, limiting luminal acidification by proton pumps. Therefore, we investigated whether NHE6 expression altered APP localization and processing in a stably transfected cell culture model of human APP expression. We show that co-expression with NHE6 shifts APP away from trans Golgi network into early and recycling endosomes in HEK293 cells. NHE6 alkalinized the endosomal lumen and significantly attenuated APP processing and Aβ secretion. To rule out non-specific overexpression effects we examined the effects of NHE6 mutations associated with neurodegeneration, which we predicted to result in loss of function by mapping on to the three dimensional homology model of NHE6 generated based on the template structure of E. coli NhaA. Finally, we show that NHE6 transcript and protein levels are lowered in post-mortem Alzheimer's brains relative to age-matched control brains. Patients with mutations in NHE6 show progressive neurodegeneration and tau pathologies. These observations, taken together with emerging evidence from genome wide association studies, suggest that endosomal Na+/H+ exchangers act as proton leak pathways that regulate Aβ generation and contribute to disease etiology. We suggest that therapeutic elevation of endosomal pH using mildly alkalinizing drugs or by enhancing NHE6 activity will significantly reduce amyloid and tau pathologies.