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Team:UCL/Background
From 2013.igem.org
RESEARCH
Alzheimer's Disease
Dementia is an age related neurodegenerative condition, characterised by failure of recent memory and intellectual functions (attention, language, visual-spatial orientation, abstract thinking, judgement), and tends to progress steadily. These changes are due to the mounting dysfunction and death of brain cells, called neurons, that are responsible for the storage and computation of information. Late stages of the disease often see patients bedridden, mute and incontinent. Although some drugs can temporarily improve memory, pharmaceutical research, through enlightening, has been clinically unsuccessful. At present there are no treatments that can halt, let alone revert, the inexorable progression of dementia.
Alzheimer’s disease is the most common of the dementias, afflicting 5-10% of the US population over 45, and 2% of the population in industrialised countries (Mattson 2004). It is predicted that its incidence will rocket up threefold 50 years from now (http://www.alz.org). It is mainly ‘late-onset’, arising after the age of 60, though rarer early onset types exist. Because there are other forms of dementia and other means of memory impairment, AD can only be verified post-mortem by examining the deceased’s brain.
Neuropathology
There are many vying hypotheses which postulate how Alzheimer’s Disease (AD) may arise. Of these, the most well known is the Amyloid Hypothesis, which is centred around the ‘senile plaques’ that form in AD brains and suggests that their removal could be key in halting the progression of the disease, though other hypotheses are contradict this precept. AD is generally accepted to cause three major histopathological changes in brain tissue.
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Histopathology
Senile plaques are extracellular deposits of an abnormal form of the waste protein β-amyloid (Aβ), which tangle with cell matter in the brain. These plaques are larger than cell bodies (15-25 um in diameter) and mature to become even denser. The tangling of the plaques, however, is not proportional to the amount of amyloid proteins in an area, and so the process by which the tangling and the plaques are created are still as yet unknown. Aβ is cleaved from a larger precursor protein - amyloid precursor protein (APP).
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Genetics
Studying the genetics of Alzheimer’s Disease has uncovered key genetic risk factors. Down’s Syndrome is caused by having three copies of chromosome 21, meaning a duplication of the APP gene. Having an extra copy of the APP gene may increase production of beta-amyloid, triggering the chain of biological events leading to AD. Early onset AD is a component of Down Syndrome, indicating that defects in chromosome 21 can lead to Alzheimer’s independently of Downs syndrome.
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Amyloid Hypothesis
It has been more than two decades since the first postulation that AD may be caused by deposition of Aβ in plaques in brain tissue. The concomitant signs and symptoms of the disease are thought to arise directly and indirectly due to these plaques, which appear in quantity in older brains and the genetically susceptible, due to an imbalance in Aβ deposition and clearance.
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