Dataset Information

Proteomics Time-Course Study of App Knock-In Mice Reveals Novel Presymptomatic A?42-Induced Pathways to Alzheimer's Disease Pathology.

ABSTRACT:

Background

The 42 amino acids long amyloid-? peptide, A?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 A?42-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 A?42 without A?PP 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 A? 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 A?42 levels initiate a cascade of events that eventually manifests in amyloid depositions, inflammation, and decline in memory.

SUBMITTER: Schedin-Weiss S

PROVIDER: S-EPMC7902969 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

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

Schedin-Weiss Sophia S Nilsson Per P Sandebring-Matton Anna A Axenhus Michael M Sekiguchi Misaki M Saito Takashi T Winblad Bengt B Saido Takaomi T Tjernberg Lars O LO

Journal of Alzheimer's disease : JAD 20200101 1

<h4>Background</h4>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.<h4>Objective</h4>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.<h4>Metho ...[more]

PMID: 32280097

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Project description:BackgroundAβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer's disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD.MethodsCSF, serum, and brain tissue were collected from 3- to 18-month-old AppNL-F/NL-F knock-in mice (n = 48) and 2-18-month-old AppNL/NL knock-in mice (n = 35). The concentrations of Aβ42 and Aβ40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral Aβ plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of Aβ42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay.ResultsIn AppNL-F/NL-F knock-in mice, Aβ42/Aβ40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral Aβ pathology, in which a more widespread Aβ plaque burden and increased levels of Aβ42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, Aβ42/Aβ40 ratios in CSF and serum showed a negative hyperbolic association with cerebral Aβ plaque burden as well as the levels of both soluble and insoluble Aβ42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral Aβ plaque pathology were found in AppNL/NL knock-in mice during the observation time.ConclusionsOur findings suggest a temporal sequence of events in AppNL-F/NL-F knock-in mice, in which initial deposition of Aβ aggregates in the brain is followed by a decline of the Aβ42/Aβ40 ratio in CSF and serum once the cerebral Aβ pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral Aβ pathology when assessed in CSF compared with serum.