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Genetic loci modulating amyloid-beta levels in a mouse model of Alzheimer's disease.

ABSTRACT: Genetic studies have demonstrated very high heritability for Alzheimer's disease (AD) risk in humans; however, these genetic contributions have proven extremely challenging to map in large studies of AD patients. Processing of the amyloid precursor protein (APP) to produce amyloid-beta (Abeta) peptide is increasingly believed to be of central importance in AD pathogenesis. Intriguingly, mice from the C57BL/6J and DBA2/J inbred strains carrying the R1.40 APP transgene produce identical levels of unprocessed APP, but demonstrate significant, heritable differences in Abeta levels. To identify specific loci responsible for the observed genetic control of Abeta metabolism in this model system, we have performed a whole-genome quantitative trait locus (QTL) mapping experiment on a total of 516 animals from a C57BL/6JxDBA/2J intercross using a dense set of SNP genetic markers. Our studies have identified three loci on mouse chromosomes 1, 2, and 7 showing significant or suggestive associations with brain Abeta levels, several of which contain regions syntenic to previous reports of linkage in human AD.

SUBMITTER: Ryman D

PROVIDER: S-EPMC3745768 | biostudies-other | 2008 Aug

REPOSITORIES: biostudies-other

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Genetic loci modulating amyloid-beta levels in a mouse model of Alzheimer's disease.

Ryman Davis D Gao Yuan Y Lamb Bruce T BT

Neurobiology of aging 20070402 8

Genetic studies have demonstrated very high heritability for Alzheimer's disease (AD) risk in humans; however, these genetic contributions have proven extremely challenging to map in large studies of AD patients. Processing of the amyloid precursor protein (APP) to produce amyloid-beta (Abeta) peptide is increasingly believed to be of central importance in AD pathogenesis. Intriguingly, mice from the C57BL/6J and DBA2/J inbred strains carrying the R1.40 APP transgene produce identical levels of ...[more]

PMID: 17400334

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Project description:BackgroundPesticide residues have contaminated our environment and nutrition over the last century. Although these compounds are present at very low concentrations, their long-term effects on human health is of concern. The link between pesticide residues and Alzheimer's disease is not clear and difficult to establish. To date, no in vivo experiments have yet modeled the impact of this chronic contamination on neurodegenerative disorders.ObjectivesWe investigated the impact of fungicide residues on the pathological markers of Alzheimer's disease in a transgenic mouse model.MethodsTransgenic (J20, hAPPSw/Ind) mice were chronically exposed to a cocktail of residues of cyprodinil, mepanipyrim, and pyrimethanil at 0.1μg/L in their drinking water for 9 months. We assessed the effects of fungicide residues on the pathological markers of the disease including Aβ aggregates, neuroinflammation, and neuronal loss. Then, we studied the dynamics of Aβ aggregation in vivo via a longitudinal study using two-photon microscopy. Finally, we investigated the molecular mechanisms involved in the production and clearance of Aβ peptides.ResultsWe found that a chronic exposure to three fungicide residues exacerbated aggregation, microgliosis, and neuronal loss. These fungicides also increased vascular amyloid aggregates reminiscent of cerebral amyloid angiopathy between 6 and 9 months of treatment. The mechanism of action revealed that fungicides promoted Aβ peptide fibril formation in vitro and involved an in vivo overexpression of the levels of the β-secretase-cleaving enzyme (BACE1) combined with impairment of Aβ clearance through neprylisin (NEP).ConclusionsChronic exposure of the J20 mouse model of Alzheimer's disease to a cocktail of fungicides, at the regulatory concentration allowed in tap water (0.1μg/L), strengthened the preexisting pathological markers: neuroinflammation, Aβ aggregation, and APP β-processing. We hypothesize prevention strategies toward pesticide long-term exposure may be an alternative to counterbalance the lack of treatment and to slow down the worldwide Alzheimer's epidemic. https://doi.org/10.1289/EHP5550.

Dataset Information

Genetic loci modulating amyloid-beta levels in a mouse model of Alzheimer's disease.

Publications

Genetic loci modulating amyloid-beta levels in a mouse model of Alzheimer's disease.

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