Early-onset FAD (familial Alzheimer's disease) is caused by mutations of PS1 (presenilin 1), PS2 (presenilin 2) and APP (amyloid precursor protein). Beyond the effects of PS1 mutations on proteolytic functions of the γ-secretase complex, mutant or deficient PS1 disrupts lysosomal function and Ca2+ homoeostasis, both of which are considered strong pathogenic factors in FAD. Loss of PS1 function compromises assembly and proton-pumping activity of the vacuolar-ATPase on lysosomes, leading to defective lysosomal acidification and marked impairment of autophagy. Additional dysregulation of cellular Ca2+ by mutant PS1 in FAD has been ascribed to altered ion channels in the endoplasmic reticulum; however, rich stores of Ca2+ in lysosomes are also abnormally released in PS1-deficient cells secondary to the lysosomal acidification defect. The resultant rise in cytosolic Ca2+ activates Ca2+-dependent enzymes, contributing substantially to calpain overactivation that is a final common pathway leading to neurofibrillary degeneration in all forms of AD (Alzheimer's disease). In the present review, we discuss the close inter-relationships among deficits of lysosomal function, autophagy and Ca2+ homoeostasis as a pathogenic process in PS1-related FAD and their relevance to sporadic AD.
Conference Article| November 20 2013
Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime
Ralph A. Nixon
Ralph A. Nixon 1
*Center for Dementia Research, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, U.S.A.
†Department of Psychiatry, New York University Langone Medical Center, 550 1st Avenue, New York, NY 10016, U.S.A.
‡Department of Cell Biology, New York University Langone Medical Center, 550 1st Avenue, New York, NY 10016, U.S.A.
1To whom correspondence should be addressed (firstname.lastname@example.org).
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MaryKate McBrayer, Ralph A. Nixon; Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime. Biochem Soc Trans 1 December 2013; 41 (6): 1495–1502. doi: https://doi.org/10.1042/BST20130201
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