Toward more predictive genetic mouse models of Alzheimer's disease

Onos, Kristen D.; Rizzo, Stacey J. Sukoff; Howell, Gareth R.; Sasner, Michael

doi:10.1016/j.brainresbull.2015.12.003

Cited by 138 publications

(123 citation statements)

References 80 publications

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“…Lack of Congo red staining suggested that degree of amyloid accumulation is not as high in this Sgo1 −/+ model as existing EOAD mouse models that typically express a few‐to‐several‐fold amount of total amyloids compared with controls and show Congo red staining (Kitazawa et al., 2012; Onos et al., 2016; Sasaguri et al., 2016). The result was in agreement with immunoblots in Figure 1 indicating only mild increase in total amyloids (amyloid‐β and APP combined) in Sgo1 −/+ compared with age‐matched wild type and BubR1 −/+ .…”

Section: Resultsmentioning

confidence: 99%

“…Major pathological features of the human AD brain include plaques of amyloid‐β made of cleaved APP, tangles of Tau proteins, and congophilic cerebral amyloid angiopathy (Kitazawa, Medeiros, & Laferl, 2012; Onos, Sukoff Rizzo, Howell, & Sasner, 2016; Sasaguri et al., 2016; Scheltens et al., 2016). With insufficient knowledge on the cause, modeling LOAD in rodents has been an issue.…”

Section: Introductionmentioning

confidence: 99%

“…Normally, mice do not develop AD, which has been interpreted as due to their shorter lifespan and sequence differences in APP and Tau. Various transgenic mouse models with modified APP, Tau, and others have been developed for EOAD (Kitazawa et al., 2012; Onos et al., 2016; Sasaguri et al., 2016). However, LOAD models are limited to apes and are practically nonexistent in rodents.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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SummarySpontaneous 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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…APB Tg .Mx −/+ mice. Several mouse models of AD have successfully shown extensive amyloid plaque deposition and neuroinflammation, but, in the absence of additional genetic manipulations, not many show significant neuronal loss and associated cognitive decline (Onos et al, 2015, Webster et al, 2014, Wirths and Bayer, 2010). The lack of substantial neuronal cell loss significantly limits the identification and testing of therapeutic targets for AD (Onos et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Meox2 haploinsufficiency increases neuronal cell loss in a mouse model of Alzheimer's disease

Soto

Grabowska

Onos

et al. 2016

Neurobiology of Aging

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Evidence suggests that multiple genetic and environmental factors conspire together to increase susceptibility to Alzheimer's disease (AD). The amyloid cascade hypothesis states that deposition of the amyloid-β peptide is central to AD; however, evidence in humans and animals suggests that amyloid-β build-up alone is not sufficient to cause neuronal cell loss and cognitive decline. Mouse models that express high levels of mutant forms of amyloid precursor protein (APP) and/or cleaving enzymes deposit amyloid but do not show neuron loss. Therefore, a double-hit hypothesis for AD has been proposed whereby vascular dysfunction precedes and promotes amyloid-β toxicity. In support of this, copy number variations in mesenchyme homeobox 2 (MEOX2), a gene involved in vascular development, are associated with severe forms of AD. However, the role of MEOX2 in AD has not been studied. Here, we tested Meox2 haploinsufficiency in B6.APP/PS1 (B6.APBTg) mice, a mouse model of AD. Despite no overt differences in plaque deposition or glial activation, B6.APBTg mice that carry only one copy of Meox2 (B6.APBTg.Mx−/+) show increased neuronal cell loss, particularly in regions containing plaques, compared to B6.APBTg mice. Neuronal cell loss corresponds with a significant decrease in plaque-associated microvessels, further supporting a synergistic effect of vascular compromise and amyloid deposition on neuronal cell dysfunction in AD.

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“…Decades of research using AD mouse models have failed to translate into successful treatments for a variety of reasons, many of which have been discussed previously (Onos et al, 2016). Our results demonstrate that genetic variation profoundly affects the expressivity of the 5XFAD transgene on both cognitive and pathological traits.…”

Section: Importance Of Genetic Background In Choosing a Mouse Modelmentioning

confidence: 99%

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

Neuner

Hohman

Richholt

et al. 2017

Preprint

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SummaryIdentifying genes that modify symptoms of Alzheimer's disease (AD) will provide novel therapeutic strategies to prevent, cure or delay AD. To discover genetic modifiers of AD, we combined a mouse model of AD with a genetically diverse reference panel to generate F1 mice harboring identical 'high-risk' human AD mutations but which differ across the remainder of their genome. We first show that genetic variation profoundly modifies the impact of causal human AD mutations and validate this panel as an AD model by demonstrating a high degree of phenotypic, transcriptomic, and genetic overlap with human AD. Genetic mapping was used to identify candidate modifiers of cognitive deficits and amyloid pathology, and viral-mediated knockdown was used to functionally validate Trpc3 as a modifier of AD. Overall, work here introduces a 'humanized' mouse population as an innovative and reproducible resource for the study of AD and identifies Trpc3 as a novel therapeutic target.

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Toward more predictive genetic mouse models of Alzheimer's disease

Cited by 138 publications

References 80 publications

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

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

Meox2 haploinsufficiency increases neuronal cell loss in a mouse model of Alzheimer's disease

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

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