Calcium Dysregulations and Autophagy Impairment in Familial Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is a common form of dementia that involves slowly developing and ultimately fatal neurodegeneration. The etiology of AD is unknown, however, the inherited cases of familial AD (FAD) caused by the mutation in presenilins (PS1, PS2) share the same neuropathological hallmarks with the sporadic AD. Their consistent phenotypes suggest they may share the same pathophysiological origins. Thus, insights into the molecular mechanisms and cellular functions of mutant PS associated with FAD are likely to provide clues into the etiology of AD. Several hypotheses have been proposed to describe the pathogenic mechanisms for FAD. While accumulation of amyloidogenic Ab plaques is a well-defined proximal feature that causes neural toxicity leading to brain pathology, another hypothesis suggests that dysregulation of calcium (Ca2+) homeostasis plays a central role in AD pathogenesis. A considerable body of evidence has demonstrated that FAD-linked PS mutations affect cellular Ca2+ homeostasis. We have demonstrated a molecular interaction between inositol trisphosphate receptor (InsP3R) and PS where mutant PS exerted stimulatory effect on InsP3R to enhance its channel activity in response to InsP3 and resulting in exaggerated Ca2+ release. However, how disrupted Ca2+ homeostasis impinges on AD pathology is still largely unknown. Recently, we identified a molecular interaction between PS1 and lysosomal two-pore channel (TPC2). FAD-linked PS1 mutation (PS1-M146L) disrupted the lysosomal Ca2+ homeostasis and thereby deranged the acidification of lysosome. The resulting increased lysosomal pH could lead to the accumulation of autophagic vacuoles and may suggest a novel molecular mechanism for autophagic pathology in AD.