Proteomics Time-Course Study of App Knock-In Mice Reveals Novel Presymptomatic Aβ42-Induced Pathways to Alzheimer's Disease Pathology.

Autor:	Schedin-Weiss S; Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden., Nilsson P; Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden., Sandebring-Matton A; Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden.; Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden., Axenhus M; Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden., Sekiguchi M; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Japan., Saito T; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Japan.; Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Science, Nagoya, Japan., Winblad B; Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden., Saido T; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Japan., Tjernberg LO; Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden.
Jazyk:	angličtina
Zdroj:	Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2020; Vol. 75 (1), pp. 321-335.
DOI:	10.3233/JAD-200028
Abstrakt:	Background: The 42 amino acids long amyloid-β peptide, Aβ42, 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 Aβ42-induced AD related mechanisms, we performed a brain proteomics time-course study on a novel App knock-in AD mouse model, AppNL-F, expressing high levels of Aβ42 without AβPP overexpression artifacts. Methods: Hippocampus and cortex were analyzed separately by using 18O-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 AppNL-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 AppNL-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 Aβ42 levels initiate a cascade of events that eventually manifests in amyloid depositions, inflammation, and decline in memory.
Databáze:	MEDLINE
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