Link between Down syndrome, Alzheimer's disease discovered
2011-01-13 16:00:00 [sifi news]
Researchers have discovered that the genetic mechanism which destroys brain cells is responsible for early development of Alzheimer's Disease in people with Down Syndrome and for development of Alzheimer's Disease in general population.
This discovery by researchers at the University of British Columbia and Vancouver Coastal Health Research Institute provides a potential new target for drugs that could forestall dementia in people with either condition.
The research, led by Dr. Weihong Song, Canada Research Chair in Alzheimer's Disease and a professor of psychiatry in the UBC Faculty of Medicine, found that excessive production of a protein, called Regulator of Calcineurin 1 (RCAN1), sets in motion a chain reaction that kills neurons in the hippocampus and cortex in people with Down Syndrome (DS) and Alzheimer's Disease (AD).
"Neuronal death is the primary reason for the memory loss and other cognitive impairments of Alzheimer's Disease, and it's the main reason people with Down Syndrome develop Alzheimer's Disease long before most people, usually in their 30s," said Song, a member of the Brain Research Centre at UBC and the Vancouver Coastal Health Research Institute (VCHRI), and Director of Townsend Family Laboratories at UBC.
People with DS have an extra copy of the gene that produces RCAN1, thus leading to its excess production. The resulting neuronal death - with symptoms that mirror those of AD patients - is one of the prime reasons for the shortened lifespan of people with DS.
The research team discovered that some AD patients have similarly elevated levels of the RCAN1 protein, despite having two copies of the responsible gene. It's still unknown why, though Song speculates that the gene's overexpression might be triggered by stroke, hypertension or the presence of a neurotoxic protein, called beta amyloid, that typically collects into clumps in the brains of people with AD - what he describes as a "vicious cycle" in which one destructive factor exacerbates another.
The findings have been published online in the Journal of Biological Chemistry. (ANI)
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Abstract from jbc.org
Regulator of calcineurin 1 (RCAN1) facilitates neuronal apoptosis through caspase 3 activation
Xiulian Sun1, Yili Wu1, Bin Chen1, Zhuohua Zhang2, Weihui Zhou1, Yigang Tong1, Jungying Yuan3, Kun Xia4, Hinrich Gronemeyer5, Richard A. Flavell6 and Weihong Song7,*
+ Author Affiliations
1 UBC, Canada;
2 Burnham Institute, United States;
3 Harvard Medical School, United States;
4 NLMG, China;
5 Inserm, France;
6 Yale, United States;
7 The University of British Columbia, Canada
* Corresponding author; email: weihong@exchange.ubc.ca
Abstract
Individuals with Down syndrome (DS) will inevitably develop Alzheimer's Disease (AD) neuropathology sometime after middle age, which may be attributable to genes triplicated in individuals with DS. The characteristics of AD neuropathology include neuritic plaques, neurofibrillary tangles and neuronal loss in various brain regions. The mechanism underlying neurodegeneration in AD and DS remains elusive. Regulators of calcineurin (RCAN1) has been implicated in the pathogenesis of DS. Our data show that RCAN1 expression is elevated in the cortex of DS and AD patients. RCAN1 expression can be activated by the stress hormone dexamethasone. A functional glucocorticoid response element (GRE) was identified in RCAN1 isoform 1(RCAN1-1) promoter region which is able to mediate the upregulation of RCAN1 expression. Here we show that overexpression of RCAN1-1 in primary neurons activates caspase-9 and caspase-3, and subsequently induces neuronal apoptosis. Furthermore, we found that the neurotoxicity of RCAN1-1 is inhibited by knockout of caspase-3 in caspase-3-/- neurons. Our study provides a novel mechanism by which RCAN1 functions as a mediator of stress and Abeta-induced neuronal death and overexpression of RCAN1 due to an extra copy of RCAN1 gene on chromosome 21 contributes to AD pathogenesis in DS.
Alzheimers disease Apoptosis Caspase Neurodegeneration Transcription Down syndrome RCAN1
Received August 23, 2010.
Accepted January 7, 2011.
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