APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

Molecular Neurodegeneration

Mitsuru Shinohara¹  Zonghua Li²  Na Zhao²  Francis Shue³  Guojun Bu³ 

[1] Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, 7-430 Morioka, 474-8511, Obu, Aichi, Japan;Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA;Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA;Neuroscience Graduate Program, Mayo Clinic, Jacksonville, FL, USA;

关键词: Apolipoprotein E2;    Alzheimer’s disease;    Amyloid-β;    Cerebrovascular disease;    Lipid metabolism;    Longevity;    Neuroinflammation;    Neurofibrially tangles;    TDP-43;    α-Synuclein;   

DOI  :  10.1186/s13024-020-00413-4

来源: Springer

【 摘 要 】

Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer’s disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition, APOE*ε2 has been identified as a longevity gene, suggesting a systemic effect of APOE*ε2 on the aging process. However, APOE*ε2 is not entirely benign; APOE*ε2 carriers exhibit increased risk of certain cerebrovascular diseases and neurological disorders. Here, we review evidence from both human and animal studies demonstrating the protective effect of APOE*ε2 against AD and propose a working model depicting potential underlying mechanisms. Finally, we discuss potential therapeutic strategies designed to leverage the protective effect of APOE2 to treat AD.

【 授权许可】

CC BY