000			02058 am a22002053u 4500
042			_adc
100	1	0	_aPrasad, Hari _eauthor _92657
700	1	0	_aRao, Rajini _eauthor _92658
245	0	0	_aEndosomal Acid-Base Homeostasis in Neurodegenerative Diseases
260			_c2020-08-01.
500			_a/pmc/articles/PMC7614123/
500			_a/pubmed/32737755
520			_aNeurodegenerative disorders are debilitating and largely untreatable conditions that pose a significant burden to affected individuals and caregivers. Overwhelming 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 ε4 allele of Apolipoprotein E (ApoE4), which potentiates pre-symptomatic endosomal dysfunction and prominent amyloid beta (Aβ) 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 Aβ pathologies. By functioning as a dominant leak pathway for protons, the Na(+)/H(+) exchanger activity of NHE6 limits endosomal acidification and regulates β-secretase (BACE)-mediated Aβ production and LRP1 receptor- mediated Aβ clearance. Pathological endosomal acidification may impact both Aβ 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.
540			_a
546			_aen
690			_aArticle
655	7		_aText _2local
786	0		_nRev Physiol Biochem Pharmacol
856	4	1	_uhttp://dx.doi.org/10.1007/112_2020_25 _zConnect to this object online.
999			_c942 _d942