Molecular mapping of alzheimer‐type dementia in Down's syndrome

Prasher, V. P.; Farrer, Matthew J.; Kessling, Anna M.; Fisher, Elizabeth; West, Ruth; Barber, P. C.; Butler, Alain

doi:10.1002/ana.410430316

Cited by 351 publications

(245 citation statements)

References 14 publications

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“…Triplication of the App gene in DS appears critical for the manifestation of AD, and is further supported by data showing that a 78 year-old DS individual with partial trisomy 21 and only two copies of App did not develop AD [61]. Moreover, trisomy of App and only a few flanking genes causes early-onset AD [65].…”

Section: Introductionmentioning

confidence: 66%

In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model

Chen

Dyakin

Branch

et al. 2009

Neurobiology of Aging

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In vivo quantitative magnetic resonance imaging (MRI) was employed to detect brain pathology and map its distribution within control, disomic mice (2N) and in Ts65Dn and Ts1Cje trisomy mice with features of human Down syndrome (DS). In Ts65Dn, but not Ts1Cje mice, transverse proton spinspin (T 2 ) relaxation time was selectively reduced in the medial septal nucleus (MSN) and in brain regions that receive cholinergic innervation from the MSN, including the hippocampus, cingulate cortex, and retrosplenial cortex. Basal forebrain cholinergic neurons (BFCNs) in the MSN, identified by choline acetyltransferase (ChAT) and nerve growth factor receptors p75 NTR and TrkA immunolabeling were reduced in Ts65Dn brains and in situ acetylcholinesterase (AChE) activity was depleted distally along projecting cholinergic fibers, and selectively on pre-and post-synaptic profiles in these target areas. T 2 effects were negligible in Ts1Cje mice that are diploid for APP and lack BFCN neuropathology, consistent with the suspected relationship of this pathology to increased App dosage. These results establish the utility of quantitative MRI in vivo for identifying Alzheimer's disease-relevant cholinergic changes in animal models of DS and the selective vulnerability of cholinergic neuron subpopulations.

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Section: Introductionmentioning

confidence: 66%

In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model

Chen

Dyakin

Branch

et al. 2009

Neurobiology of Aging

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“…This individual did not show any signs of AD, neither neuropsychological nor neuropathological, at her death at age 78 years. 19 In conclusion, we screened a collection of patients from Sweden and Finland with AD and onset at or before 65 years of age, but found no cases of APP duplications. We therefore conclude that duplication of the APP gene is not a common cause of EOAD in Swedish and Finnish populations.…”

Section: Discussionmentioning

confidence: 90%

Low prevalence of APP duplications in Swedish and Finnish patients with early-onset Alzheimer's disease

et al. 2007

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Familial early-onset Alzheimer's disease with cerebral amyloid angiopathy (EOAD/CAA) was recently associated with duplications of the gene for the amyloid-b precursor protein (APP). In this study, we have screened for duplications of APP in patients with EOAD from Sweden and Finland. Seventy-five individuals from families with EOAD and 66 individuals with EOAD without known familial inheritance were screened by quantitative PCR. On the basis of the initial results, a portion of the samples was also investigated with quantitative multiplex PCR. No duplications of APP were identified, whereby we conclude that this is not a common cause of EOAD in the Swedish and Finnish populations, at least not in our collection of families and cases.

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“…Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplication of APP (Dup-APP) -also develop EOAD [8][9][10][11][12][13][14][15] . Conversely, partial trisomy of chromosome 21 that does not result in the presence of an extra APP does not lead to AD 16,17 . Several additional genes on chromosome 21 are proposed to modulate the course of AD-DS, but further work is required to determine their role and relative importance.…”

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confidence: 96%

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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Molecular mapping of alzheimer‐type dementia in Down's syndrome

Cited by 351 publications

References 14 publications

In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model

In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model

Low prevalence of APP duplications in Swedish and Finnish patients with early-onset Alzheimer's disease

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

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