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The etiology and pathogenesis of Alzheimer's disease |
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@St@George-Hyslop@PH |
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| iCentre for Research in Neurodegenerative Diseases, University of Toronto, Toronto Western Research Institute, Toronto Western Hospitalj | ||
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| Alzheimer Disease (AD), like several other adult onset neurodegenerative diseases, is a multi-@factorial illness with both genetic and non-genetic causes. Recent genetic studies have clearly identified four genes associated with inherited risk for AD (presenilin1-PS1 ; presenilin 2-PS2 ; amyloid precursor protein-APP ; apolipoprotein E-APOE). These four genes account for about half of the total risk genetic risk for AD. Ongoing attempts to clone the remaining AD-susceptibility genes have to date provided tentative evidence for genes on chromosome 12, chromosome 10, and possibly on chromosomes 9 and 18. The identity of these genes remains unknown. Several other candidate genes have been implicated on the basis of positive case : control allelic association studies, but the results of these association studies have not generally been widely replicated. Consequently, the true role for the majority of these other candidate genes currently remains unclear. Nevertheless, biological studies on the four validated AD-causing genes have helped depict a biochemical pathway that is activated by mutations in these genes. It seems that mutations in all of the four known AD-genes alter the production and/or clearance of Aΐ peptide, a proteolytic cleavage product of the APP protein. When taken together, these results imply that the accumulation of Aΐ within the brain is an important early and initiating event, at least in genetic cases, and probably also in sporadic cases. It remains unclear exactly how the accumulation of Aΐ is related to the accumulation of phosphorylated tau in neurofibrillary tangles (another neuropathological hallmark of AD). However, the discovery that polymorphisms/mutations in the tau gene are associated with inherited forms of frontotemporal dementia, as well as risk for progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) implies that misprocessing of the tau microtubule associated protein can also cause neurodegeneration. This convincingly argues that misprocessing of tau is itself a significantly deleterious biochemical event, and is not merely an innocent secondary/bystander effect. These results provide several important practical and theoretical advances. First, knowledge of the pathways generating Aΐ and causing accumulation of tau protein, now provide rational therapeutic targets (e.g. inhibitors of the enzymes producing Aΐ, antibodies and small molecules inhibiting Aΐ fibril assembly and toxicity, etc.). Secondly, these observations have also uncovered novel biological mechanisms such as Α-mediated cleavage of Type 1 transmembrane proteins (termed regulated intramembranous proteolysis). This latter process appears to have an essential role in such diverse biological events as Notch signal transduction during development, and the production of Aΐ in adult-onset AD. During the next few years, further advances will occur that will clarify the functional relationships between the genesis of Aΐ and the accumulation of tau in neurofibrillary tangles. Additionally, it is likely that several of the therapeutic targets defined by the recent work described above will be brought to clinical trials, and will therefore allow us to directly test these hypothese. |
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