Presenilin is essential for ApoE secretion, a novel role of presenilin involved in Alzheimer's disease pathogenesis

Alzheimer disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-p-protein (A beta) into amyloid plaques in patient brain. Mutations in presenilin (PS) lead to abnormal generation of A beta, which is the major cause of familial AD (FAD) and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of gamma-secretase activity. Blockade of gamma-secretase activity by a gamma-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of gamma-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin (NCT) deficient cells with reduced gamma-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin alpha 4, a nuclear-transport receptor. Moreover, expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal controls. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion. Significance Statement FAD typically results from mutations in the genes encoding amyloid precursor protein (APP), PS1 or PS2. Many PS mutants have been found to exert impaired y-secretase activity and increased A beta 42/A beta 40 ratio, which induce early amyloid deposition and FAD. On the other hand, ApoE4 is the major genetic risk factor for SAD and contributes to AD pathogenesis because it has reduced A beta clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms, however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretion in vitro and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.

Automated summary

This study found that presenilin (PS) plays an important role in the pathogenesis of sporadic AD (SAD) by regulating the secretion of apolipoprotein E (ApoE). PS deficiency leads to decreased ApoE secretion, and PS mutants affect ApoE secretion. These findings reveal a novel mechanism by which PS is involved in SAD pathogenesis.