TY - JOUR
T1 - Presenilin 1 phosphorylation regulates amyloid-β degradation by microglia
AU - Ledo, Jose Henrique
AU - Liebmann, Thomas
AU - Zhang, Ran
AU - Chang, Jerry C.
AU - Azevedo, Estefania P.
AU - Wong, Eitan
AU - Silva, Hernandez Moura
AU - Troyanskaya, Olga G.
AU - Bustos, Victor
AU - Greengard, Paul
N1 - Funding Information:
Acknowledgements This work was supported by funds received from Fisher Center for Alzheimer′s Research Foundation, JPB Foundation, and Cure Alzheimer’s Fund. JHL is a Pew Latin American Fellow in the Biomedical Sciences, supported by The Pew Charitable Trusts. OGT and RZ were in part supported by the US National Institutes of Health (NIH) grant R01 GM071966. OGT is a senior fellow of the Genetic Networks program of the Canadian Institute for Advanced Research (CIFAR). We thank Drs. Marc Flajolet and Jean-Pierre Roussarie, for discussions and critical reading and editing of the manuscript. We thank Dr. Kunihiro Uryu, the director of the Electron Microscopy Resource Center and Dr. Connie Zhao, the director of Genomics Resource Center, both at Rockefeller University, for their valuable assistance with experiments. We also thank Dr. Alison North and Dr. Kaye Thomas at Bio-Imaging Resource Center for their assistance using the multiphoton microscope. The Rockefeller University Bio-Imaging Resource Center is supported by the Empire State Stem Cell Fund through NYSDOH C023046. This work is dedicated to the memory of Paul Greengard, beloved mentor and fantastic scientist.
Publisher Copyright:
© 2020, The Author(s).
PY - 2021/10
Y1 - 2021/10
N2 - Amyloid-β peptide (Aβ) accumulation in the brain is a hallmark of Alzheimer’s Disease. An important mechanism of Aβ clearance in the brain is uptake and degradation by microglia. Presenilin 1 (PS1) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the maturation of multiple substrates, such as Aβ. Although PS1 has been extensively studied in neurons, the role of PS1 in microglia is incompletely understood. Here we report that microglia containing phospho-deficient mutant PS1 display a slower kinetic response to micro injury in the brain in vivo and the inability to degrade Aβ oligomers due to a phagolysosome dysfunction. An Alzheimer’s mouse model containing phospho-deficient PS1 show severe Aβ accumulation in microglia as well as the postsynaptic protein PSD95. Our results demonstrate a novel mechanism by which PS1 modulates microglial function and contributes to Alzheimer’s -associated phenotypes.
AB - Amyloid-β peptide (Aβ) accumulation in the brain is a hallmark of Alzheimer’s Disease. An important mechanism of Aβ clearance in the brain is uptake and degradation by microglia. Presenilin 1 (PS1) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the maturation of multiple substrates, such as Aβ. Although PS1 has been extensively studied in neurons, the role of PS1 in microglia is incompletely understood. Here we report that microglia containing phospho-deficient mutant PS1 display a slower kinetic response to micro injury in the brain in vivo and the inability to degrade Aβ oligomers due to a phagolysosome dysfunction. An Alzheimer’s mouse model containing phospho-deficient PS1 show severe Aβ accumulation in microglia as well as the postsynaptic protein PSD95. Our results demonstrate a novel mechanism by which PS1 modulates microglial function and contributes to Alzheimer’s -associated phenotypes.
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U2 - 10.1038/s41380-020-0856-8
DO - 10.1038/s41380-020-0856-8
M3 - Article
C2 - 32792660
AN - SCOPUS:85089401462
SN - 1359-4184
VL - 26
SP - 5620
EP - 5635
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 10
ER -