Abstract
The development of effective therapies as well as early, molecular diagnosis of Alzheimer's disease is impeded by the lack of understanding of the underlying pathological mechanisms. Metabolomics studies of body fluids as well as brain tissues have shown major changes in metabolic profiles of Alzheimer's patients. However, with analysis performed at the late stages of the disease it is not possible to distinguish causes and consequence. The mouse model APP/PS1 expresses a mutant amyloid precursor protein resulting in early Amyloid β (Aβ) accumulation as well as many resulting physiological changes including changes in metabolic profile and metabolism. Analysis of metabolic profile of cerebrospinal fluid (CSF) and blood of APP/PS1 mouse model can provide information about metabolic changes in these body fluids caused by Aβ accumulation. Using our novel method for analysis of correlation and mathematical ranking of significant correlations between metabolites in CSF and blood, we have explored changes in metabolite correlation and connectedness in APP/PS1 and wild type mice. Metabolites concentration and correlation changes in CSF, blood and across the blood brain barrier determined in this work are affected by the production of amyloid plaque. Metabolite changes observed in the APP/PS1 mouse model are the response to the mutation causing plaque formation, not the cause for the plaque suggesting that they are less relevant in the context of early treatment and prevention then the metabolic changes observed only in humans.
Highlights
Alzheimer’s disease (AD) is an age-related, degenerative brain disease characterized by progressive cognitive impairment and dementia with increasing deficiency in multiple cognitive domains including memory, executive functions and language [1]
Comparison of the metabolic profiles of cerebrospinal fluid (CSF) and blood at different time points in male and female mice from the amyloid precursor protein/presenilin 1 (APP/PS1) mouse model has been used to investigate metabolic changes induced by the production of amyloid plaque
The novel approach for the analysis of correlation between metabolites in the CSF and blood has shown changes in the number of significant correlations across the blood brain barrier for a number of metabolites indicated for their importance in AD, such as ascorbate, pantothenic acid, glucose 1-phosphate, glyceric acid and creatine
Summary
Alzheimer’s disease (AD) is an age-related, degenerative brain disease characterized by progressive cognitive impairment and dementia with increasing deficiency in multiple cognitive domains including memory, executive functions and language [1]. Pathological hallmarks of AD are neurofibrillary tangles composed of abnormally phosphorylated, conformed and truncated tau, and senile plaques with a core of the altered cleavage of amyloid precursor protein leading to the deposition of β-amyloid. In addition several other anomalies have been observed. Metabolomics analysis in Alzheimer mouse model a4fe-7d160ffb36b1 (DOI: https://doi.org/10.4224/ 40002051) Blood metabolic profiles: CPMG experiment:https://nrc-digital-repository.canada.ca/ eng/view/object/?id=0ace4911-a04b-40d9-8d4a7933df6b064b and this information has been added to the manuscript. Metabolomics analysis in Alzheimer mouse model a4fe-7d160ffb36b1 (DOI: https://doi.org/10.4224/ 40002051) Blood metabolic profiles: CPMG experiment:https://nrc-digital-repository.canada.ca/ eng/view/object/?id=0ace4911-a04b-40d9-8d4a7933df6b064b and this information has been added to the manuscript. (DOI: https://doi.org/10. 4224/40002050)
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