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Proteomics Time-Course Study of App Knock-In Mice Reveals Novel Presymptomatic Aβ(42)-Induced Pathways to Alzheimer’s Disease Pathology

BACKGROUND: The 42 amino acids long amyloid-β peptide, Aβ(42), may initiate a cascade of events leading to the severe neurodegeneration observed in Alzheimer’s disease (AD) brain. However, the underlying molecular mechanisms remain to be established. OBJECTIVE: To find early Aβ(42)-induced AD relate...

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Detalles Bibliográficos
Autores principales: Schedin-Weiss, Sophia, Nilsson, Per, Sandebring-Matton, Anna, Axenhus, Michael, Sekiguchi, Misaki, Saito, Takashi, Winblad, Bengt, Saido, Takaomi, Tjernberg, Lars O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902969/
https://www.ncbi.nlm.nih.gov/pubmed/32280097
http://dx.doi.org/10.3233/JAD-200028
Descripción
Sumario:BACKGROUND: The 42 amino acids long amyloid-β peptide, Aβ(42), may initiate a cascade of events leading to the severe neurodegeneration observed in Alzheimer’s disease (AD) brain. However, the underlying molecular mechanisms remain to be established. OBJECTIVE: To find early Aβ(42)-induced AD related mechanisms, we performed a brain proteomics time-course study on a novel App knock-in AD mouse model, App(NL-F), expressing high levels of Aβ(42) without AβPP overexpression artifacts. METHODS: Hippocampus and cortex were analyzed separately by using (18)O-labelling mass spectrometry to reveal alterations in protein levels. Pathway analysis of proteomics data was used to identify altered biological functions. Immunohistochemistry was used to further investigate a significant key regulatory protein. RESULTS: Around 100 proteins were differently expressed in App(NL-F) mice at each time point (3, 6, 9, and 18 months of age) as compared to wild type mice. Strikingly, already at 3 months of age—long before Aβ plaque development and memory impairment—several pathways, including long-term potentiation and synaptic plasticity, were downregulated, and neuritogenesis was increased. Huntingtin (HTT) was identified as an upstream regulator, i.e., a key protein affecting the levels of several proteins. Increased levels of HTT in hippocampus of App(NL-F) mice was supported by immunofluorescence microscopy. CONCLUSION: Notably, the proteome was significantly altered already at 3 months of age, 6 months before the development of plaques. Differentially expressed proteins varied over time, indicating that increased Aβ(42) levels initiate a cascade of events that eventually manifests in amyloid depositions, inflammation, and decline in memory.