Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of<i>APP</i>

Wiseman, Frances K.; Lj, Pulford; Barkus, Christopher; Liao, Fan; Portelius, Erik; Webb, Robin L.; Chávez‐Gutiérrez, Lucía; Cleverley, Karen; S, Noy; Sheppard, Olivia; Collins, Toby; Powell, Caroline; Cj, Sarell; Rickman, Matthew; Choong, Xun Yu; Jl, Tosh; Siganporia, C; Whittaker, Heather; Stewart, Floy R.; Szaruga, María; Murphy, Michele; Blennow, Kaj; Strooper, Bart De; Zetterberg, Henrik; Bannerman, David M.; Dm, Holtzman; Vlj, Tybulewicz; Fisher, Elizabeth

doi:10.1093/brain/awy159

Cited by 98 publications

(89 citation statements)

References 67 publications

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“…A recent report on a mouse model of triplication of chromosome 21 genes other than APP supports the presence of an effect of aneuploidy on amyloid‐beta accumulation. The mice showed increased amyloid‐beta aggregation and deposition of plaques with cognitive deficits, although they showed no increase in APP abundance (Wiseman et al, ).…”

Section: The “Amyloid‐beta Accumulation Cycle”mentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

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The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

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Section: The “Amyloid‐beta Accumulation Cycle”mentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

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“…Although some chromosomal rearrangement and deletions have been identified in the construction process, it has allowed exploration of the relationship between specific Hsa21 genes (including those not found in the mouse) and phenotype . Whilst amyloid precursor protein (APP) is known to significantly contribute to the early‐onset of Alzheimer disease, recently it has been shown that triplication of other genes on Hsa21 (Tc1 mouse is 75% trisomic for Hsa21 genes) can exacerbate plaque formation and cognitive deficits in mice . Advances in chromosomal engineering have facilitated the design of more specific mouse models which include duplications of entire syntenic segments of Mmu16 (Dp[16]1Yey)/Dp16 (B6.129S7‐Dp[16Lipi‐Zbtb21]1Yey/J) and Dp1Tyb (Dp[16Lipi‐Zbtb21]1TybEmcf)], Mmu17 (Dp[17]1Yey), and Mmu10 (Dp[10]Yey).…”

Section: Mouse Models Of Down Syndromementioning

confidence: 99%

“…3,57,67 Whilst amyloid precursor protein (APP) is known to significantly contribute to the early-onset of Alzheimer disease, recently it has been shown that triplication of other genes on Hsa21 (Tc1 mouse is 75% trisomic for Hsa21 genes) can exacerbate plaque formation and cognitive deficits in mice. 68 Advances in chromosomal engineering have facilitated the design of more specific mouse models which include duplications of entire syntenic segments of Mmu16 (Dp [16] 1Yey)/Dp16 (B6.129S7-Dp[16Lipi-Zbtb21]1Yey/J) and Dp1Tyb (Dp[16Lipi-Zbtb21]1TybEmcf)], Mmu17 (Dp [17] 1Yey), and Mmu10 (Dp[10]Yey). This has led to the development of the most complete 'triple trisomic mouse' which develops Down syndrome-related neurological impairments.…”

Section: Mouse Models Of Down Syndromementioning

confidence: 99%

New approaches to studying early brain development in Down syndrome

Baburamani

Patkee

Arichi

et al. 2019

Develop Med Child Neuro

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Down syndrome is the most common genetic developmental disorder in humans and is caused by partial or complete triplication of human chromosome 21 (trisomy 21). It is a complex condition which results in multiple lifelong health problems, including varying degrees of intellectual disability and delays in speech, memory, and learning. As both length and quality of life are improving for individuals with Down syndrome, attention is now being directed to understanding and potentially treating the associated cognitive difficulties and their underlying biological substrates. These have included imaging and postmortem studies which have identified decreased regional brain volumes and histological anomalies that accompany early onset dementia. In addition, advances in genome‐wide analysis and Down syndrome mouse models are providing valuable insight into potential targets for intervention that could improve neurogenesis and long‐term cognition. As little is known about early brain development in human Down syndrome, we review recent advances in magnetic resonance imaging that allow non‐invasive visualization of brain macro‐ and microstructure, even in utero. It is hoped that together these advances may enable Down syndrome to become one of the first genetic disorders to be targeted by antenatal treatments designed to ‘normalize’ brain development. What this paper adds Magnetic resonance imaging can provide non‐invasive characterization of early brain development in Down syndrome. Down syndrome mouse models enable study of underlying pathology and potential intervention strategies. Potential therapies could modify brain structure and improve early cognitive levels. Down syndrome may be the first genetic disorder to have targeted therapies which alter antenatal brain development.

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“…The assumption that triplication of the APP gene causes AD pathology in DS is in line with rare case studies of individuals with partial trisomy of chromosome 21 who have only two copies of the APP gene, where post‐mortem neuropathological examinations revealed normal age‐related changes but no evidence of AD neuropathology (Doran et al, ; Prasher et al, ). However, the triplication of other genes on chromosome 21 aside from APP could also play a role in AD pathogenesis, as is suggested by findings of (a) differing amyloid deposition in animal model studies depending on the extent of the triplication (Wiseman et al, ), and (b) the apparent clinical and neuropathological differences between individuals with AD due to full trisomy 21 and those with the rare copy number variant resulting in APP duplication (Zis & Strydom, ).…”

Section: Introductionmentioning

confidence: 99%

Plasma amyloid and tau as dementia biomarkers in Down syndrome: Systematic review and meta‐analyses

Alhajraf

Ness

Hye

et al. 2019

Developmental Neurobiology

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Individuals with Down syndrome (DS) are at high risk of developing Alzheimer's disease (AD). Discovering reliable biomarkers which could facilitate early AD diagnosis and be used to predict/monitor disease course would be extremely valuable. To examine if analytes in blood related to amyloid plaques may constitute such biomarkers, we conducted meta‐analyses of studies comparing plasma amyloid beta (Aβ) levels between DS individuals and controls, and between DS individuals with and without dementia. PubMed, Embase, and Google Scholar were searched for studies investigating the relationship between Aβ plasma concentrations and dementia in DS and 10 studies collectively comprising >1,600 adults, including >1,400 individuals with DS, were included. RevMan 5.3 was used to perform meta‐analyses. Meta‐analyses showed higher plasma Aβ40 (SMD = 1.79, 95% CI [1.14, 2.44], Z = 5.40, p < .00001) and plasma Aβ42 levels (SMD = 1.41, 95% CI [1.15, 1.68], Z = 10.46, p < .00001) in DS individuals than controls, and revealed that DS individuals with dementia had higher plasma Aβ40 levels (SMD = 0.23, 95% CI [0.05, 0.41], Z = 2.54, p = .01) and lower Aβ42/Aβ40 ratios (SMD = −0.33, 95% CI [−0.63, −0.03], Z = 2.15, p = .03) than DS individuals without dementia. Our results indicate that plasma Aβ40 levels may constitute a promising biomarker for predicting dementia status in individuals with DS. Further investigations using new ultra‐sensitive assays are required to obtain more reliable results and to investigate to what extent these results may be generalizable beyond the DS population.

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Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy ofAPP

Cited by 98 publications

References 67 publications

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

New approaches to studying early brain development in Down syndrome

Plasma amyloid and tau as dementia biomarkers in Down syndrome: Systematic review and meta‐analyses

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