Open AccessProteomics Time-Course Study of App Knock-In Mice Reveals Novel Presymptomatic Aβ42-Induced Pathways to Alzheimer’s Disease Pathology
Author(s) -
Sophia SchedinWeiss,
Per Nilsson,
Anna SandebringMatton,
Michael Axenhus,
Masaki Sekiguchi,
Takashi Saito,
Bengt Winblad,
Takaomi C. Saido,
Lars O. Tjernberg
Publication year - 2020
Publication title -
journal of alzheimer's disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.677
H-Index - 139
eISSN - 1875-8908
pISSN - 1387-2877
DOI - 10.3233/jad-200028
Subject(s) - neurodegeneration , proteome , proteomics , biology , hippocampus , amyloid precursor protein , alzheimer's disease , amyloid beta , amyloid (mycology) , neuroscience , microbiology and biotechnology , pathology , disease , medicine , bioinformatics , peptide , biochemistry , botany , gene
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.