Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis

Wilcock, Donna M.; Griffin, W. Sue T.

doi:10.1186/1742-2094-10-84

Cited by 187 publications

(204 citation statements)

References 136 publications

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“…Individuals with DS are at an increased risk of immune system dysfunction: these individuals have a higher incidence of both autoimmune and infectious disease 191 , and show upregulation of pro-inflammatory makers, including interleukin-1, in the brain 192,193 . This dysregulation may contribute to AD-DS through alterations in microglial activation 190 .…”

Section: Immune System Dysfunctionmentioning

confidence: 99%

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: Immune System Dysfunctionmentioning

confidence: 99%

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

et al. 2015

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“…However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and to the development of Alzheimer's disease (AD) neuropathology. The primary hallmarks of AD, such as the accumulation of amyloid plaques composed of β-amyloid (Aβ) peptides, neurofibrillary tangles (NFTs) formed by insoluble deposits of abnormally hyperphosphorylated tau, neuroinflammation, synapse and neuron loss and regional atrophy, are present in 100% of individuals with DS by the fourth decade of life (Wilcock and Griffin, 2013;Lott, 2012;Cenini et al, 2012;Sabbagh et al, 2011;Lott and Dierssen, 2010;Teipel and Hampel, 2006).…”

Section: Introductionmentioning

confidence: 99%

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

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“…It has been reported that there are more than 217,800 cases a year across the world. The clinical picture of this syndrome is complex; more than 80 phenotypes have been observed in individuals, including intellectual disabilities with delayed learning and cognition, congenital anomalies such as congenital heart disease and childhood leukemia, and the appearance of an Alzheimer-like disease during aging (Fillon-Emery et al, 2004;Duchon et al, 2011;Wilcock et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Inheritance of balanced translocation t(17; 22) from a Down syndrome mother to a phenotypically normal daughter

et al. 2015

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ABSTRACT. We report that a 30-year-old woman with mental retardation was referred for prenatal diagnoses during pregnancy. An ultrasound scan showed that the heart structure and function of the fetus were normal. Cytogenetic analysis showed that the female karyotype was 47,XX, t(17; 22) (q21; q11), +21. The woman's husband had a normal male karyotype and was phenotypically normal. During this first pregnancy, an amniocentesis, which was done at 19 weeks, revealed that the fetal karyotype was 46,XX, t(17; 22) (q21; q11). Fluorescence in situ hybridization testing of amniotic fluid gave a normal result for chromosome 21. The child was a phenotypically normal female baby.

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Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis

Cited by 187 publications

References 136 publications

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

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

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

Inheritance of balanced translocation t(17; 22) from a Down syndrome mother to a phenotypically normal daughter

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