Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer’s Disease Pathogenesis

Sadequl Islam, Yang Sun, Yuan Gao, Tomohisa Nakamura, Arshad Ali Noorani, Tong Li, Philip C. Wong, Noriyuki Kimura, Etsuro Matsubara, Kensaku Kasuga, Takeshi Ikeuchi, Taisuke Tomita, Kun Zou, Makoto Michikawa

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer’s disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-b (Ab) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Ab, 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 c-secretase activity. Blockade of c-secretase activity by a c-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of c-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced c-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin a4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.

Original languageEnglish (US)
Pages (from-to)1574-1586
Number of pages13
JournalJournal of Neuroscience
Volume42
Issue number8
DOIs
StatePublished - Feb 23 2022

Keywords

  • apolipoprotein E
  • familial AD
  • presenilin
  • secretion
  • sporadic AD

ASJC Scopus subject areas

  • General Neuroscience

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