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Association between Alzheimer's disease pathogenesis and early demyelination and oligodendrocyte dysfunction.

ABSTRACT: The APPSwe/PSEN1dE9 (APP/PS1) transgenic mouse model is an Alzheimer's disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer's disease. Previous clinical autopsy and imaging studies suggest that Alzheimer's disease patients have white matter and oligodendrocyte damage, but the underlying mechanisms of these have not been revealed. Therefore, the present study used APP/PS1 mice to assess cognitive change, myelin loss, and corresponding changes in oligodendrocytes, and to explore the underlying mechanisms. Morris water maze tests were performed to evaluate cognitive change in APP/PS1 mice and normal C57BL/6 mice aged 3 and 6 months. Luxol fast blue staining of the corpus callosum and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for myelin basic protein (MBP) mRNA were carried out to quantify myelin damage. Immunohistochemistry staining for NG2 and qRT-PCR for monocarboxylic acid transporter 1 (MCT1) mRNA were conducted to assess corresponding changes in oligodendrocytes. Our results demonstrate that compared with C57BL/6 mice, there was a downregulation of MBP mRNA in APP/PS1 mice aged 3 months. This became more obvious in APP/PS1 mice aged 6 months accompanied by other abnormalities such as prolonged escape latency in the Morris water maze test, shrinkage of the corpus callosum, upregulation of NG2-immunoreactive cells, and downregulation of MCT1 mRNA. These findings indicate that the involvement of early demyelination at 3 months and the oligodendrocyte dysfunction at 6 months in APP/PS1 mice are in association with Alzheimer's disease pathogenesis.

SUBMITTER: Dong YX

PROVIDER: S-EPMC5998637 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Association between Alzheimer's disease pathogenesis and early demyelination and oligodendrocyte dysfunction.

Dong Yu-Xia YX Zhang Hui-Yu HY Li Hui-Yuan HY Liu Pei-Hui PH Sui Yi Y Sun Xiao-Hong XH

Neural regeneration research 20180501 5

The APPSwe/PSEN1dE9 (APP/PS1) transgenic mouse model is an Alzheimer's disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer's disease. Previous clinical autopsy and imaging studies suggest that Alzheimer's disease patients have white matter and oligodendrocyte damage, but the underlying mechanisms of these have not been revealed. Therefore, the present study used APP/PS1 mice to assess cognitive change, myelin l ...[more]

PMID: 29863022

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Project description:Alzheimer's disease (AD) is the most common form of dementia and the leading risk factor, after age, is possession of the apolipoprotein E epsilon 4 allele (APOE4). Approximately 50% of AD patients carry one or two copies of APOE4 but the mechanisms by which it confers risk are still unknown. APOE4 carriers are reported to demonstrate changes in brain structure, cognition, and neuropathology, but findings have been inconsistent across studies. In the present study, we used multi-modal data to characterise the effects of APOE4 on the brain, to investigate whether AD pathology manifests differently in APOE4 carriers, and to determine if AD pathomechanisms are different between carriers and non-carriers. Brain structural differences in APOE4 carriers were characterised by applying machine learning to over 2000 brain MRI measurements from 33,384 non-demented UK biobank study participants. APOE4 carriers showed brain changes consistent with vascular dysfunction, such as reduced white matter integrity in posterior brain regions. The relationship between APOE4 and AD pathology was explored among the 1260 individuals from the Religious Orders Study and Memory and Aging Project (ROSMAP). APOE4 status had a greater effect on amyloid than tau load, particularly amyloid in the posterior cortical regions. APOE status was also highly correlated with cerebral amyloid angiopathy (CAA). Bulk tissue brain transcriptomic data from ROSMAP and a similar dataset from the Mount Sinai Brain Bank showed that differentially expressed genes between the dementia and non-dementia groups were enriched for vascular-related processes (e.g., "angiogenesis") in APOE4 carriers only. Immune-related transcripts were more strongly correlated with AD pathology in APOE4 carriers with some transcripts such as TREM2 and positively correlated with pathology severity in APOE4 carriers, but negatively in non-carriers. Overall, cumulative evidence from the largest neuroimaging, pathology, and transcriptomic studies available suggests that vascular dysfunction is key to the development of AD in APOE4 carriers. However, further studies are required to tease out non-APOE4-specific mechanisms.

Dataset Information

Association between Alzheimer's disease pathogenesis and early demyelination and oligodendrocyte dysfunction.

Publications

Association between Alzheimer's disease pathogenesis and early demyelination and oligodendrocyte dysfunction.

Similar Datasets

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