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Biochemical characteristics
Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded amyloid beta protein in the brains of AD patients. Amyloid beta, also written A?, is a short peptide that is a proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation. Although amyloid beta monomers are soluble and harmless, they undergo a dramatic conformational change at sufficiently high concentration to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils that deposit outside neurons in dense formations known as senile plaques or neuritic plaques, in less dense aggregates as diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or congophilic angiopathy.
AD is also considered a tauopathy due to abnormal aggregation of the tau protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton. Like most microtubule-associated proteins, tau is normally regulated by phosphorylation; however, in AD patients, hyperphosphorylated tau accumulated as paired helical filaments that in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques.
Neuropathology
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains. At an anatomical level, AD is characterized by gross diffuse atrophy of the brain and loss of neurons, neuronal processes and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Levels of the neurotransmitter acetylcholine are reduced. Levels of the neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Glutamate levels are usually elevated.
Disease mechanism
Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is known as the "cholinergic hypothesis" and suggests that AD is due to reduced biosynthesis of the neurotransmitter acetylcholine. The medications that treat acetylcholine deficiency have served to only treat symptoms of the disease and have neither halted nor reversed it. The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholingeric effects have been proposed to initiate large-scale aggregation leading to generalized neuroinflammation.
Research after 2000 includes hypotheses centered on the effects of the misfolded and aggregated proteins, amyloid beta and tau. The two positions differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other believes that beta amyloid deposits are the causative factor in the disease. The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques do not correlate well with neuron loss; however, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.
The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on chromosome 21, and patients with trisomy 21 - better known as Down syndrome - who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age. The traditional formulation of the amyloid hypothesis points to the cytotoxicity of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing apoptosis. A more recent and widely supported hypothesis suggests that the cytotoxic species is an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an oligomeric species. Relevantly, much early development work on lead compounds has focused on the inhibition of fibrillization, but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.
It should be noted further that ApoE4, the major genetic risk factor for AD, leads to excess amyloid build up in the brain before AD symptoms arise. Thus, beta-amyloid deposition precedes clinical AD.[30] Another strong support for the amyloid hypothesis, which looks at the beta-amyloid as the common initiating factor for the Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop first diffuse and then fibrillar beta-amyloid plaques, associated with neuronal and microglial damage.
Genetics
Rare cases of Alzheimer's are caused by dominant genes that run in families. These cases often have an early age of onset. Mutations in presenilin-1 or presenilin-2 genes have been documented in some families. Mutations of presenilin 1 (PS1) lead to the most aggressive form of familial Alzheimer's disease (FAD). Evidence from rodent studies suggests that the FAD mutation of PS1 results in impaired hippocampal-dependent learning which is correlated with reduced adult neurogenesis in the dentate gyrus. Mutations in the APP gene on chromosome 21 can also cause early onset disease. The presenilins have been identified as essential components of the proteolytic processing machinery that produces beta amyloid peptides through cleavage of APP.
Most cases identified are "sporadic" with no clear family history. Environmental factors sometimes claimed to increase risk of Alzheimer's include prior head injury, particularly repeated trauma, previous incidents of migraine headaches, exposure to defoliants, and low activity levels during adulthood. However, with the exception of previous concussion, none of these environmental risk factors are widely accepted.
Inheritance of the ?4 allele of the ApoE gene is regarded as a risk factor for development of disease, but large-scale genetic association studies raise the possibility that even this does not indicate susceptibility so much as how early one is likely to develop Alzheimer's. There is speculation among genetic experts that there are other risk and protective factor genes that may influence the development of late onset Alzheimer's disease (LOAD). Researchers are investigating the possibility that the regulatory regions of various Alzheimer's associated genes could be important in sporadic Alzheimer's, especially inflammatory activation of these genes. These hypotheses include the amyloid-? precursor protein (APP), the beta secretase enzymes insulin-degrading enzyme endothelin-converting enzymes and inflammatory 5-lipoxygenase gene.
Genetic linkage
Alzheimer's disease is definitely linked to the 1st, 14th, and 21st chromosomes, but other linkages are controversial and not, as yet, confirmed. While some genes predisposing to AD have been identified , such as ApoE4 on chromosome 19, sporadic AD also involves other risk and protective genes still awaiting confirmation.
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