A Human Stem Cell Model of Early Alzheimer’s Disease Pathology in Down Syndrome

Shi, Yunfeng; Kirwan, Peter; Smith, James; MacLean, Glenn; Orkin, Stuart H.; Livesey, Frederick J.

doi:10.1126/scitranslmed.3003771

Cited by 263 publications

(246 citation statements)

References 37 publications

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“…However, increased levels of soluble Aβ 42 are found in ~50% of trisomy 21 fetal brains 118 , suggesting that APP may be dosage sensitive during fetal development of individuals with DS but that this change may not be sufficient to cause extensive Aβ deposition in the developing brain -perhaps because of efficient clearance. Consistent with this, overexpression of APP and/or increased levels of Aβ have been reported in trisomy 21 human cell models, including in induced pluripotent stem cells (iPSCs) derived from infants or young adults with DS [119][120][121][122] . Although triplication of APP does not necessarily lead to enhanced expression of APP and subsequent increase in Aβ accumulation in all contexts, overexpression of APP is strongly linked to Aβ deposition in adult life.…”

Section: Triplication Of Appmentioning

confidence: 65%

“…Several genes involved in neurodevelopment have been suggested to have an important role in AD (including components of the WNT and reelin signalling pathway 201,202 ). Additionally, cultures of cells derived from infants with Down syndrome (DS) show clear overexpression of amyloid precursor protein (APP) [119][120][121][122] , and amyloid-β (Aβ) plaques have been found in the brains of children with DS who are as young as 8 years of age 65 . Thus, the syndrome offers a longitudinal perspective on the multilevel effects of Aβ and tau pathology during development.…”

Section: Identifying Risk and Protective Factors For Ad In Young Chilmentioning

confidence: 99%

“…Consistent with this, an increase in the ratio of 3R/4R tau has been reported to occur in AD-DS, as compared with LOAD or age-matched euploid individuals without dementia 179,180 . Additionally, an increase in the total amount of tau has been reported in the cortex in AD-DS as compared with that in age-matched euploid individuals without dementia, and in DS iPSC-derived neurons 122,179 ; this upregulation may be the result of increased APP levels 181 . DYRK1A also downregulates the levels of neural restrictive silencing factor (NRSF; also known as REST), a neuroprotective protein 168,169 , which has reduced expression in people with AD 182 .…”

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A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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Section: Triplication Of Appmentioning

confidence: 65%

Section: Identifying Risk and Protective Factors For Ad In Young Chilmentioning

confidence: 99%

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confidence: 99%

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A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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“…We show that, although many neuronal characteristics appear normal, Ts21 iPSCderived neurons display a significant synaptic deficit that is present in both glutamatergic and GABAergic subtypes. Recently, the work by Shi et al (57) reported "normal" synaptic activity in glutamatergic neurons differentiated from a single Ts21 iPSC line. However, the absence of GABAergic neurons in their system and diminutive excitatory synaptic currents (<5 pA) suggest aberrant network formation as well.…”

Section: Discussionmentioning

confidence: 99%

Deficits in human trisomy 21 iPSCs and neurons

Weick

Held

Bonadurer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

175

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Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability, but the precise molecular mechanisms underlying impaired cognition remain unclear. Elucidation of these mechanisms has been hindered by the lack of a model system that contains full trisomy of chromosome 21 (Ts21) in a human genome that enables normal gene regulation. To overcome this limitation, we created Ts21-induced pluripotent stem cells (iPSCs) from two sets of Ts21 human fibroblasts. One of the fibroblast lines had low level mosaicism for Ts21 and yielded Ts21 iPSCs and an isogenic control that is disomic for human chromosome 21 (HSA21). Differentiation of all Ts21 iPSCs yielded similar numbers of neurons expressing markers characteristic of dorsal forebrain neurons that were functionally similar to controls. Expression profiling of Ts21 iPSCs and their neuronal derivatives revealed changes in HSA21 genes consistent with the presence of 50% more genetic material as well as changes in non-HSA21 genes that suggested compensatory responses to oxidative stress. Ts21 neurons displayed reduced synaptic activity, affecting excitatory and inhibitory synapses equally. Thus, Ts21 iPSCs and neurons display unique developmental defects that are consistent with cognitive deficits in individuals with Down syndrome and may enable discovery of the underlying causes of and treatments for this disorder.cerebral cortex | developmental disorders D own syndrome (DS) is the most frequent single cause of human birth defects and intellectual disability (ID) (1). DS is caused by trisomy of chromosome 21 (Ts21) (2), resulting in the triplication of over 400 genes (3-5), which makes elucidation of the precise mechanisms underlying ID in DS a significant challenge. Confounding this difficulty is the relative inaccessibility of human tissue and incomplete human Ts21 in the context of mouse models. Despite these shortcomings, studies using mouse models containing trisomy of parts of syntenic chromosome 21 (HSA21) have put forth several critical hypotheses on the cellular and molecular mechanisms underlying DS features. It is essential, however, to test these hypotheses in human cells with full triplication of HSA21 in a context that allows for normal gene regulation. Here, we used Ts21-induced pluripotent stem cells (iPSCs) to test hypotheses of the underlying causes of ID in DS, with specific regard to neuropathophysiology. ResultsIsogenic Human Ts21 iPSCs. Fibroblasts from two individuals diagnosed with DS were reprogrammed to iPSCs. FISH for HSA21 in one fibroblast line showed mosaicism, where ∼90% of cells carried Ts21, whereas ∼10% were euploid (Fig. 1A). Reprogramming of the mosaic fibroblasts by retrovirus (6) resulted in three viable iPSC clones, two clones that carried Ts21 and one euploid (Fig. 1B). Mosaicism in DS individuals is rare, occurring in ∼1-3% of DS cases (7), but it can also emerge in vitro (8), potentially because of nondisjunction events during cell division.

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“…Furthermore, genetic and epigenetic variability among patients may influence pharmacological responsiveness [45]. Disease modeling using iPS cells for AD has been actively pursued recently and has shown that pharmacological assays can be readily performed using these models [46][47][48][49][50][51][52]. Modeling and screening using glial-neuron coculture and 3-dimensional cultures, both of which better resemble in vivo physiological states, should also be pursued [53,54].…”

Section: Phenotypic Approachesmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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A Human Stem Cell Model of Early Alzheimer’s Disease Pathology in Down Syndrome

Cited by 263 publications

References 37 publications

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Deficits in human trisomy 21 iPSCs and neurons

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

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