TY - JOUR
T1 - ApoE4 attenuates autophagy via FoxO3a repression in the brain
AU - Sohn, Hee Young
AU - Kim, Seong Ik
AU - Park, Jee Yun
AU - Park, Sung Hye
AU - Koh, Young Ho
AU - Kim, Joon
AU - Jo, Chulman
N1 - Funding Information:
We thank Drs. Gail VW Johnson (University of Rochester, USA), Michael Greenberg (Harvard Medical School, USA) and Peter Davies (Albert Einstein College of Medicine, USA) for providing materials for this study. This research was supported by a fund (2019-NI-086-02) from Research of Korea Disease Control and Prevention Agency.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Apolipoprotein E (ApoE) plays multiple roles in lipid transport, neuronal signaling, glucose metabolism, mitochondrial function, and inflammation in the brain. It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the ε4 allele of APOE is the highest genetic risk factor for developing late-onset Alzheimer’s disease (AD). However, the mechanism by which ApoE4 contributes to the pathogenesis of AD remains unclear. We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the APOE4 allele.
AB - Apolipoprotein E (ApoE) plays multiple roles in lipid transport, neuronal signaling, glucose metabolism, mitochondrial function, and inflammation in the brain. It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the ε4 allele of APOE is the highest genetic risk factor for developing late-onset Alzheimer’s disease (AD). However, the mechanism by which ApoE4 contributes to the pathogenesis of AD remains unclear. We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the APOE4 allele.
UR - http://www.scopus.com/inward/record.url?scp=85114595678&partnerID=8YFLogxK
U2 - 10.1038/s41598-021-97117-6
DO - 10.1038/s41598-021-97117-6
M3 - Article
C2 - 34475505
AN - SCOPUS:85114595678
VL - 11
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 17604
ER -
