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Spontaneous development of Alzheimer's disease-associated brain pathology in a Shugoshin-1 mouse cohesinopathy model.

ABSTRACT: Spontaneous late-onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early-onset AD (EOAD) models that rely on forcible expression of AD-associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials. In this study, we hypothesized that genomic instability facilitates development of LOAD and tested two genomic instability mice models in the brain pathology at the old age. Shugoshin-1 (Sgo1) haploinsufficient (?) mice, a model of chromosome instability (CIN) with chromosomal and centrosomal cohesinopathy, spontaneously exhibited a major feature of AD pathology; amyloid beta accumulation that colocalized with phosphorylated Tau, beta-secretase 1 (BACE), and mitotic marker phospho-Histone H3 (p-H3) in the brain. Another CIN model, spindle checkpoint-defective BubR1-/+ haploinsufficient mice, did not exhibit the pathology at the same age, suggesting the prolonged mitosis-origin of the AD pathology. RNA-seq identified ten differentially expressed genes, among which seven genes have indicated association with AD pathology or neuronal functions (e.g., ARC, EBF3). Thus, the model represents a novel model that recapitulates spontaneous LOAD pathology in mouse. The Sgo1-/+ mouse may serve as a novel tool for investigating mechanisms of spontaneous progression of LOAD pathology, for early diagnosis markers, and for drug development.

SUBMITTER: Rao CV

PROVIDER: S-EPMC6052391 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Spontaneous development of Alzheimer's disease-associated brain pathology in a Shugoshin-1 mouse cohesinopathy model.

Rao Chinthalapally V CV Farooqui Mudassir M Zhang Yuting Y Asch Adam S AS Yamada Hiroshi Y HY

Aging cell 20180625 4

Spontaneous late-onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early-onset AD (EOAD) models that rely on forcible expression of AD-associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limi ...[more]

PMID: 29943428

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Project description:BackgroundBased on epidemiological and experimental studies, type 2 diabetes mellitus (T2DM), especially insulin resistance that comprises the core mechanism of T2DM, has been recognized as a significant risk factor for Alzheimer's disease (AD). Studies in humans and diabetic AD model mice have indicated a correlation between insulin resistance and increased amyloid deposition in the brain. Paradoxically, mice with targeted disruption of genes involved in the insulin signaling pathway showed protective effects against the AD-related pathology. These conflicting observations raise an issue as to the relationship between dysregulation of insulin signaling and AD pathophysiology.MethodsTo study the causal relations and molecular mechanisms underlying insulin resistance-induced exacerbation of amyloid pathology, we investigated the chronological changes in the development of insulin resistance and amyloid pathology in two independent insulin-resistant AD mouse models, i.e., long-term high-fat diet (HFD) feeding and genetic disruption of Irs2, in combination with dietary interventions. In addition to biochemical and histopathological analyses, we examined the in vivo dynamics of brain amyloid-β (Aβ) and insulin by microdialysis technique.ResultsHFD-fed diabetic AD model mice displayed a reduced brain response to peripheral insulin stimulation and a decreased brain to plasma ratio of insulin during the hyperinsulinemic clamp. Diet-induced defective insulin action in the brain was accompanied by a decreased clearance of the extracellular Aβ in vivo and an exacerbation of brain amyloid pathology. These noxious effects of the HFD both on insulin sensitivity and on Aβ deposition in brains were reversibly attenuated by dietary interventions. Importantly, HFD feeding accelerated Aβ deposition also in the brains of IRS-2-deficient AD mice.ConclusionsOur results suggested a causal and reversible association of brain Aβ metabolism and amyloid pathology by diet-dependent, but not genetically-induced, insulin-resistance. These observations raise the possibility that the causal factors of insulin resistance, e.g., metabolic stress or inflammation induced by HFD feeding, but not impaired insulin signaling per se, might be directly involved in the acceleration of amyloid pathology in the brain.

Dataset Information

Spontaneous development of Alzheimer's disease-associated brain pathology in a Shugoshin-1 mouse cohesinopathy model.

Publications

Spontaneous development of Alzheimer's disease-associated brain pathology in a Shugoshin-1 mouse cohesinopathy model.

Similar Datasets

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