Identification of chromosome 21 DNA polymorphisms for genetic studies in Alzheimer's disease and Down syndrome

1991 ◽  
Vol 87 (6) ◽  
pp. 649-653 ◽  
Author(s):  
G. Van Camp ◽  
H. Backhovens ◽  
M. Cruts ◽  
A. Wehnert ◽  
W. Van Hul ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Chromosome 21 ◽  
Dna Polymorphisms ◽  
Genetic Studies

scholarly journals Genetic dissection of down syndrome-associated alterations in APP/amyloid-β biology using mouse models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Justin L. Tosh ◽  
◽  
Elena R. Rhymes ◽  
Paige Mumford ◽  
Heather T. Whittaker ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Amyloid Precursor Protein ◽  
Mouse Models ◽  
Early Onset ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
Extra Copy ◽  
Early Onset Alzheimer’S Disease

AbstractIndividuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or ‘dose’ of APP is thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer’s disease in people who have Down syndrome.

scholarly journals Endosomal structure and APP biology are not altered in preclinical cellular models of Down syndrome

2021 ◽  
Author(s):  
Claudia Cannavo ◽  
Karen Cleverley ◽  
Cheryl Maduro ◽  
Paige Mumford ◽  
Dale Moulding ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Cell Biology ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
App Processing ◽  
Cellular Models ◽  
Increased Risk ◽  
Primary Mouse

Individuals who have Down syndrome (trisomy 21) are at greatly increased risk of developing Alzheimer’s disease – dementia. Alzheimer’s disease is characterised by the accumulation in the brain of amyloid-β plaques that are a product of amyloid precursor protein, encoded by the APP gene on chromosome 21. In Down syndrome the first site of amyloid-β accumulation is within endosomes and changes to endosome biology occur early in disease. Here we determine if primary mouse embryonic fibroblasts isolated from two mouse models of Down syndrome can be used to study endosome and APP cell biology. We report that in these cellular models of Down syndrome endosome number, size and APP processing are not altered, likely because APP is not dosage sensitive in these models, despite three copies of App .

scholarly journals β-Secretases, Alzheimer’s Disease, and Down Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Robin L. Webb ◽  
M. Paul Murphy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Amyloid Precursor Protein ◽  
Healthy Aging ◽  
Precursor Protein ◽  
Chromosome 21 ◽  
Rate Limiting Step ◽  
Age Related

Individuals with Down Syndrome (DS), or trisomy 21, develop Alzheimer’s disease (AD) pathology by approximately 40 years of age. Chromosome 21 harbors several genes implicated in AD, including the amyloid precursor protein and one homologue of theβ-site APP cleaving enzyme, BACE2. Processing of the amyloid precursor protein byβ-secretase (BACE) is the rate-limiting step in the production of the pathogenic Aβpeptide. Increased amounts of APP in the DS brain result in increased amounts of Aβand extracellular plaque formation beginning early in life. BACE dysregulation potentially represents an overlapping biological mechanism with sporadic AD and a common therapeutic target. As the lifespan for those with DS continues to increase, age-related concerns such as obesity, depression, and AD are of growing concern. The ability to prevent or delay the progression of neurodegenerative diseases will promote healthy aging and improve quality of life for those with DS.

The Search for Biomarkers of Alzheimer's Disease in Down Syndrome

2020 ◽  
Vol 125 (2) ◽  
pp. 97-99 ◽  
Author(s):  
Benjamin L. Handen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Longitudinal Study ◽  
High Risk ◽  
Amyloid Precursor Protein ◽  
Current Knowledge ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
Increased Risk

Abstract Adults with Down syndrome are at high risk for Alzheimer's disease (AD), with most individuals developing clinical dementia by their late 60s. This increased risk for AD has been attributed, at least in part, to triplication and overexpression of the gene for amyloid precursor protein (APP) on chromosome 21, leading to elevated levels of amyloid β peptides. This article offers a brief overview of our current knowledge of AD in the DS population. In addition, information on a NIA/NICHD-funded, multicenter longitudinal study of biomarkers of AD in adults with DS is provided.

scholarly journals Neuroinflammation in the Aging Down Syndrome Brain; Lessons from Alzheimer's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Donna M. Wilcock
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Chromosome 21 ◽  
Pathological Changes ◽  
Genetic Changes ◽  
Course Of Disease ◽  
Complex Process ◽  
Down Syndrome Brain ◽  
The Brain

Down syndrome (DS) is the most genetic cause of mental retardation and is caused by the triplication of chromosome 21. In addition to the disabilities caused early in life, DS is also noted as causing Alzheimer's-disease-like pathological changes in the brain, leading to 50–70% of DS patients showing dementia by 60–70 years of age. Inflammation is a complex process that has a key role to play in the pathogenesis of Alzheimer's disease. There is relatively little understood about inflammation in the DS brain and how the genetics of DS may alter this inflammatory response and change the course of disease in the DS brain. The goal of this review is to highlight our current understanding of inflammation in Alzheimer's disease and predict how inflammation may affect the pathology of the DS brain based on this information and the known genetic changes that occur due to triplication of chromosome 21.

P2-121: Chromosome 21-encoded miRNA-155 upregulation and complement factor H (CFH) deficits in Down syndrome (DS) and Alzheimer's disease (AD)

2012 ◽  
Vol 8 (4S_Part_8) ◽  
pp. P303-P303 ◽  
Author(s):  
Y.Y. Li ◽  
S Bhattacharjee ◽  
J.M. Hill ◽  
P.N. Alexandrov ◽  
A.I. Pogue ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Factor H ◽  
Chromosome 21 ◽  
Complement Factor H ◽  
Complement Factor

scholarly journals Neuronal overexpression of DYRK1A/minibrain alters motor decline, neurodegeneration and synaptic plasticity in Drosophila

2018 ◽  
Author(s):  
Simon A Lowe ◽  
Maria M Usowicz ◽  
James JL Hodge
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Transmitter Release ◽  
Motor Performance ◽  
Chromosome 21 ◽  
Motor Deficits ◽  
Short Term ◽  
Age Dependent ◽  
Insight Into

AbstractDown syndrome (DS) is characterised by abnormal cognitive and motor development, and later in life by progressive Alzheimer’s disease (AD)-like dementia, neuropathology, declining motor function and shorter life expectancy. It is caused by trisomy of chromosome 21 (Hsa21), but how individual Hsa21 genes contribute to various aspects of the disorder is incompletely understood. Previous work has demonstrated a role for triplication of the Hsa21 gene DYRK1A in cognitive and motor deficits, as well as in altered neurogenesis and neurofibrillary degeneration in the DS brain, but its contribution to other DS phenotypes is unclear. Here we demonstrate that overexpression of minibrain (mnb), the Drosophila ortholog of DYRK1A, in the Drosophila nervous system accelerated age-dependent decline in motor performance and shortened lifespan. Overexpression of mnb in the eye was neurotoxic and overexpression in ellipsoid body neurons in the brain caused age-dependent neurodegeneration. At the larval neuromuscular junction, an established model for mammalian central glutamatergic synapses, neuronal mnb overexpression enhanced spontaneous vesicular transmitter release. It also slowed recovery from short-term depression of evoked transmitter release induced by high-frequency nerve stimulation and increased the number of boutons in one of the two glutamatergic motor neurons innervating the muscle. These results provide further insight into the roles of DYRK1A triplication in abnormal aging and synaptic dysfunction in DS.Author summaryDown syndrome (DS) is caused by three copies of chromosome 21 instead of the usual two. It is characterised by cognitive and motor deficits, which worsen with age resulting in Alzheimer’s disease (AD). Which genes on chromosome 21 cause these phenotypes is incompletely understood. Here we demonstrate that neuronal overexpression of minibrain, the Drosophila ortholog of the chromosome 21 gene DYRK1A, causes age-dependent degeneration of brain neurons, accelerates age-dependent decline in motor performance and shortens lifespan. It also modifies presynaptic structure, enhances spontaneous transmitter release and slows recovery from short-term depression of synaptic transmission at a model glutamatergic synapse. These findings give insight into the role of DYRK1A overexpression in aberrant aging and altered information processing in DS and AD.

scholarly journals Genetic dissection of Down syndrome-associated alterations in APP/amyloid-β biology using mouse models

2020 ◽  
Author(s):  
Justin L. Tosh ◽  
Ellie Rhymes ◽  
Paige Mumford ◽  
Heather T. Whittaker ◽  
Laura J. Pulford ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Amyloid Precursor Protein ◽  
Mouse Models ◽  
Early Onset ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
Extra Copy ◽  
Early Onset Alzheimer’S Disease

AbstractIndividuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or ‘dose’ of APP is thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer’s disease in people who have Down syndrome.

scholarly journals Adiponectin Modulation by Genotype and Maternal Choline Supplementation in a Mouse Model of Down Syndrome and Alzheimer’s Disease

2021 ◽  
Vol 10 (13) ◽  
pp. 2994
Author(s):  
Melissa J. Alldred ◽  
Sang Han Lee ◽  
Stephen D. Ginsberg
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Cognitive Decline ◽  
Genetic Disorder ◽  
Chromosome 21 ◽  
Noninvasive Treatment ◽  
Protein Levels ◽  
Potential Biomarker ◽  
Underlying Mechanisms

Down syndrome (DS) is a genetic disorder caused by the triplication of human chromosome 21, which results in neurological and physiological pathologies. These deficits increase during aging and are exacerbated by cognitive decline and increase of Alzheimer’s disease (AD) neuropathology. A nontoxic, noninvasive treatment, maternal choline supplementation (MCS) attenuates cognitive decline in mouse models of DS and AD. To evaluate potential underlying mechanisms, laser capture microdissection of individual neuronal populations of MCS offspring was performed, followed by RNA sequencing and bioinformatic inquiry. Results at ~6 months of age (MO) revealed DS mice (the well-established Ts65Dn model) have significant dysregulation of select genes within the Type 2 Diabetes Mellitus (T2DM) signaling pathway relative to normal disomic (2N) littermates. Accordingly, we interrogated key T2DM protein hormones by ELISA assay in addition to gene and encoded protein levels in the brain. We found dysregulation of adiponectin (APN) protein levels in the frontal cortex of ~6 MO trisomic mice, which was attenuated by MCS. APN receptors also displayed expression level changes in response to MCS. APN is a potential biomarker for AD pathology and may be relevant in DS. We posit that changes in APN signaling may be an early marker of cognitive decline and neurodegeneration.

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