Presenilin 1 phosphorylation regulates amyloid-β degradation by microglia
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...
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| Veröffentlicht in: | Molecular psychiatry 2021-10, Vol.26 (10), p.5620-5635 |
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| container_title | Molecular psychiatry |
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| creator | Ledo, Jose Henrique Liebmann, Thomas Zhang, Ran Chang, Jerry C. Azevedo, Estefania P. Wong, Eitan Silva, Hernandez Moura Troyanskaya, Olga G. Bustos, Victor Greengard, Paul |
| description | 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. |
| doi_str_mv | 10.1038/s41380-020-0856-8 |
| format | Article |
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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. 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The Author(s).</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular psychiatry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ledo, Jose Henrique</au><au>Liebmann, Thomas</au><au>Zhang, Ran</au><au>Chang, Jerry C.</au><au>Azevedo, Estefania P.</au><au>Wong, Eitan</au><au>Silva, Hernandez Moura</au><au>Troyanskaya, Olga G.</au><au>Bustos, Victor</au><au>Greengard, Paul</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Presenilin 1 phosphorylation regulates amyloid-β degradation by microglia</atitle><jtitle>Molecular psychiatry</jtitle><stitle>Mol Psychiatry</stitle><addtitle>Mol Psychiatry</addtitle><date>2021-10-01</date><risdate>2021</risdate><volume>26</volume><issue>10</issue><spage>5620</spage><epage>5635</epage><pages>5620-5635</pages><issn>1359-4184</issn><eissn>1476-5578</eissn><abstract>Amyloid-β peptide (Aβ) accumulation in the brain is a hallmark of Alzheimer’s Disease. 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| subjects | 13 13/106 13/31 14 14/28 14/63 14/69 38 38/91 631/378 64 64/110 64/60 692/699 Alzheimer Disease - genetics Alzheimer's disease Amyloid beta-Peptides - metabolism Amyloid beta-Protein Precursor - metabolism Amyloid Precursor Protein Secretases - metabolism Animals Behavioral Sciences Biological Psychology Brain injury Deficient mutant Medicine Medicine & Public Health Mice Microglia Microglia - metabolism Neurodegenerative diseases Neurosciences Pharmacotherapy Phenotypes Phosphorylation Postsynaptic density proteins Presenilin 1 Presenilin-1 - genetics Presenilin-1 - metabolism Psychiatry Secretase β-Amyloid |
| title | Presenilin 1 phosphorylation regulates amyloid-β degradation by microglia |
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