Endosomal Acid-Base Homeostasis in Neurodegenerative Diseases

Neurodegenerative disorders are debilitating and largely untreatable conditions that pose a significant burden to affected individuals and caregivers. Over-whelming evidence supports a crucial preclinical role for endosomal dysfunction as an upstream pathogenic hub and driver in Alzheimer's disease (AD) and related neurodegenerative disorders. We present recent advances on the role of endosomal acid-base homeostasis in neurodegeneration and discuss evidence for converging mechanisms. The strongest genetic risk factor in sporadic AD is the epsilon 4 allele of Apolipoprotein E (ApoE4), which potentiates pre-symptomatic endosomal dysfunction and prominent amyloid beta (A beta) pathology, although how these pathways are linked mechanistically has remained unclear. There is emerging evidence that the Christianson syndrome protein NHE6 is a prominent ApoE4 effector linking endosomal function to A beta pathologies. By functioning as a dominant leak pathway for protons, the Na+/H+ exchanger activity of NHE6 limits endosomal acidification and regulates beta-secretase (BACE)-mediated A beta production and LRP1 receptor-mediated A beta clearance. Pathological endosomal acidification may impact both A beta generation and clearance mechanisms and emerges as a promising therapeutic target in AD. We also offer our perspective on the complex role of endosomal acid-base homeostasis in the pathogenesis of neurodegeneration and its therapeutic implications for neuronal rescue and repair strategies.