Synaptic proteasome is inhibited in Alzheimer's disease models and associates with memory impairment in mice

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art_RIBEIRO_Synaptic_proteasome_is_inhibited_in_Alzheimers_disease_models_2023.PDF (2.56 MB)
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0
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article
Data de publicação
2023
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Scopus
Web of Science
PubMed
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NATURE PORTFOLIO
Autores
RIBEIRO, Felipe C.
COZACHENCO, Danielle
HEIMFARTH, Luana
FORTUNA, Juliana T. S.
FREITAS, Guilherme B. de
SOUSA, Jorge M. de
ALVES-LEON, Soniza V.
Citação
COMMUNICATIONS BIOLOGY, v.6, n.1, article ID 1127, 12p, 2023
Projetos de Pesquisa
Unidades Organizacionais
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Resumo
The proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer's disease (AD) post-mortem brain tissue and in experimental models. We found a marked increase in ubiquitinylated proteins in post-mortem AD hippocampi compared to controls. Using several experimental models, we show that amyloid-beta oligomers (A beta Os) inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from APPswePS1 Delta E9 mice. Reduced synaptic proteasome activity instigated by A beta Os is corrected by treatment with rolipram, a phosphodiesterase-4 inhibitor, in mice. Results further show that dynein inhibition blocks A beta O-induced reduction in dendritic proteasome content in hippocampal neurons. Finally, proteasome inhibition induces AD-like pathological features, including reactive oxygen species and dendritic spine loss in hippocampal neurons, inhibition of hippocampal mRNA translation, and memory impairment in mice. Results suggest that proteasome inhibition may contribute to synaptic and memory deficits in AD. A study involving several research models suggests that the function and synaptic localization of proteasomes, intracellular machineries involved in protein degradation, are impaired in the brains affected by Alzheimer's disease.
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https://observatorio.fm.usp.br/handle/OPI/57345
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - FM/MPT
Artigos e Materiais de Revistas Científicas - LIM/22
Artigos e Materiais de Revistas Científicas - LIM/66