Biochemistry of Alzheimer's disease
The Alzheimer's disease (AD), is one of the most common causes of adult dementia, is as yet not well understood. AD has been identified as a protein misfolding disease due to the accumulation of abnormally folded amyloid beta protein in the brains of Alzheimer's patients. Amyloid beta, also written Aβ, is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP), whose function is unclear but thought to be involved in neuronal development.
A more recent and broadly supported variation of the amyloid hypothesis identifies the cytotoxic species as an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an oligomeric species, possibly toroidal or star-shaped with a central channel that may induce apoptosis by physically piercing the cell membrane. This ion channel hypothesis postulates that oligomers of soluble, non-fibrillar Aβ form membrane ion channels allowing unregulated calcium influx into neurons. A related alternative suggests that a globular oligomer localized to dendritic processes and axons in neurons is the cytotoxic species.
Relevantly, the cytotoxic-fibril hypothesis presented a clear target for drug development: inhibit the fibrillization process. Much early development work on lead compounds has focused on this inhibition; most are also reported to reduce neurotoxicity, 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.
An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia. Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication. One receptor for Aβ oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt–Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease. One study found possible evidence of human to human transmission.
Biochemistry of Alzheimer's Disease
Alzheimer's Disease Research
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