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Delaying Alzheimer’s Disease in people with Down Syndrome

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Delaying Alzheimer’s in people with Down Syndrome

Craig Maude Psych 205 Walton 3/28/14

Delaying Alzheimer’s Disease in people with Down Syndrome

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INTRO Trisomy 21, or having a third chromosome on your 21st set of chromosomes was named Down Syndrome in 1866 by a British Doctor named Jonathan Langdon Down. Down syndrome is the most frequently occurring chromosomal disorder and the leading cause of intellectual and developmental delay in the U.S. and in the world. (Global Down Syndrome Foundation, 2011) Down syndrome is a mentally handicapping disease which affects any child born with it differently. The chances of having a child with Down syndrome are increased, but not limited to women of older age. Typically in their late 30’s or 40’s and the age factor only matters in the woman not the man. Down syndrome probability increases with advanced age in mothers. However, since younger women have more babies, 80% of newborns with Down syndrome in the US are born to mothers under 35 years old. (Global Down Syndrome Foundation, 2011) Despite being born with mentally and physical disabilities people with Down syndrome are capable of growing their IQ or increasing their muscles to fight through the physical and mental disabilities. People with Down syndrome are significantly predisposed to certain medical conditions including congenital heart defects, sleep apnea, and Alzheimer’s disease. (Global Down Syndrome Foundation, 2011) Down syndrome is a very tough mental disability that with the right medication and work can make the life of the person who has it not so tough. Down syndrome cannot be fixed, you cannot have genes altered and have the disability removed from you. Today the average lifespan of a person with Down syndrome in the U.S. is approximately 60 years, as opposed to in 1985 when the average lifespan for a person with Down syndrome was 25 years. (Global Down Syndrome Foundation, 2011) Although many people with Down syndrome can be highly impacted by their disability, they can still live successful lives like a

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typical person. Many people with Down syndrome today can live on their own and are also provided a free public education by the government. BODY One disease that overtime coincides with Down syndrome is Alzheimer’s disease. Alzheimer’s disease (AD) is the most common form of dementia. AD is a general term for memory loss and other intellectual abilities serious enough to interfere with daily life. Alzheimer's disease accounts for 50 to 80 percent of dementia cases. Even though AD greatest known risk factor is old age, usually around 65, however it is found in people with Down syndrome around the age of 40 (Shaw & Chang, 2013). As you go on living with AD it will progressively get worse over time. It will cause whoever has to experience a higher level of memory loss and make daily activities harder to accomplish. Just like Down syndrome there is no cure for AD. Virtually all Down syndrome adults develop progressive neurodegeneration as seen in Alzheimer's disease, and overexpression of the amyloid precursor protein (APP), a gene located on chromosome 21, is thought to contribute to AD in DS (Shaw & Chang, 2013) With the amount of people who have Down syndrome and the percentage of those people who develop AD, research is being conducted as an attempt to help delay the age in which AD is developed in people with Down syndrome. By creating this drug it can help people with Down syndrome have a better memory and help them live longer and be able to live on their own longer into adulthood. On the 21st chromosome we have an Amyloid Precursor Protein (APP), people with Down syndrome have an overexpression, or a little too much, of APP which is the main cause of AD in Down syndrome. Due to the three chromosomes on the 21st gene causing Down syndrome, you see where the overexpression to the APP happening. Consistently,

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duplication of a normal copy of APP is sufficient to cause familial AD confirming that it is a key gene in AD neuropathologies seen in Down syndrome (Shaw & Chang, 2013). Post-mortem brains from Down syndrome and Alzheimer's disease patients show an upregulation of the Down syndrome critical region 1 protein (DSCR1) (Shaw & Chang, 2013). This protein is found on any human regardless of having Down syndrome or not. The connection between DSCR1 and AD are not conclusive but there are small connections beginning to be made. One of the connections between AD in people with Down syndrome and DSCR1 is there is a Drosophila homolog in DSCR1 called Nebula. It delays neurodegeneration and ameliorates axonal transport defects caused by APP overexpression (Shaw & Chang, 2013). Earlier in this paper I stated that people with Down syndrome have an overexpression of APP. APP overexpressions is developed when someone is diagnosed with Down syndrome and they have their extra chromosome on the 21st set. That third part on the chromosome causes the overexpression, which in return the APP causes the DSCR1 homolog Nebula to happen. According to brainmysteries.com: "The drug we used is a specific GABA-A α5 inverse agonist (α5IA) that hypothetically could combat the abnormal neuronal excitation/inhibition balance associated with DS" This drug is being tested on mice who have Down syndrome, and it has the potential to benefit humans if it is proven successful. The a5IA molecule can potentiate learning and memory performances in cognitively-impaired DS mice. The a5IA also showed no side effects on sensory-motor and anxiety-related behaviors. Also, they found no evidence of histological changes in various organ tissues following chronic administration (Neuropsychopharmacology,
2013)

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UPDATE Since last researching this topic there have been more tests done including using mice who have been altered to have Down syndrome. There have been findings that in the mouse model of Down syndrome, hippocampal deficits of learning and memory are the most robust features supporting this mouse as a valid cognitive model of Down syndrome (Smith). “Although dentate gyrus (DG) dysfunction is suggested by excessive GABAergic inhibition, its role in perturbing DG functions in DS is unknown” (Smith). When the mouse model of DS was first created, so was a hypothesis that the specific role of the DG is disturbed in its support of contextual and spatial information. Support for this hypothesis comes from rats with DG lesions that show similar deficits. These mice have been put through a series of tests which emphasize the importance of recognizing spatial and contextual cues and that involve DG function (Smith). The results that came from this test showed that the mice are impaired in DG-dependent shortterm recognition test. Mice can recognize object novelty in the absence of contextual cues after a 5-min delay, they cannot do so after a 24 hour delay. “However the results also show that the DS mice are not impaired in tasks (object recognition and configural object recognition) that are mediated by the perirhinal cortex (PRh)” (Smith). With the DS mice not being impaired in the object recognition tasks it further proves the comparison that a mouse with DS genes relates to a human with DS, helping the tests be done that can improve short term memory loss in a human with DS. SUMMARY There are many links that connects Alzheimer’s disease with Down syndrome. When you have APP overexpression it causes the DSCR1, which is found in people with Down syndrome. With doctors working hard there could potentially be some sort of medicine created that could

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help people with Down syndrome develop Alzheimer’s later in life. With 38% of American’s knowing someone with Down syndrome, people with Down syndrome are a large part of this country (Global Down Syndrome Foundation, 2011). With the updated research on rats with the Down syndrome gene doctors are coming closer to helping delay short term memory loss and Alzheimer’s in humans with Down syndrome. The mice that are being used are showing the same impairments and difficulties as well as the same successions when doing different short term memory tasks that a human with Down syndrome has. This drug could end up very much helping people with Down syndrome not develop Alzheimer’s as early in age as it does right now which could in the long run help the mortality age of people with Down syndrome. The research being done with mice is a good sign in this drug becoming a successful and well used drug in the upcoming years. Creating this medicine will help delay the development of Alzheimer’s disease in someone with Down syndrome which will in turn help people with Down syndrome more capable of living on their own later in to their lives.

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Works Cited Global Down Syndrome Foundation (n.d.). Retrieved from http://www.globaldownsyndrome.org/about-down-syndrome/facts- about-down-syndrome/ Neuropsychopharmacology, E. C. O. (n.d.). Retrieved from http://www.brainmysteries.com/research/GABA_inverse_agonist_restores_cognitive_fun ction_in_Downs_syndrome.asp?utm_source=feedburner&utm_medium=feed&utm_cam paign=Feed: BrainMysteries (Brain News And Research)&utm_content=My Yahoo Shaw, J., & Chang, K. (2013, September 26).Nebula/dscr1 upregulation delays eurodegeneration and protects against app-induced axonal transport defects by restoring calcineurin and gsk-3β signaling. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784514/
Smith, G. (n.d.). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24339224

Unknown. (n.d.). Retrieved from

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http://www.alz.org/alzheimers_disease_what_is_alzheimers.asp