Gene expression in Alzheimer's disease.
Even though the exact cause of Alzheimer's disease is not known, it is clear that genetic factors play a major role. Screening of familial cases has so far linked four genes to Alzheimer's disease: amyloid precursor protein, presenilin 1, presenilin 2 and apolipoprotein E. Mutations in the amyloid precursor protein, presenilin 1 and presenilin 2 genes cause the enhanced production of b amyloid that is found in neuritic plaques. While apolipoprotein E allele e4 does not cause enhanced production of amyloid, it does enhance its deposition. The genes identified so far are linked to only about 10% of total Alzheimer's disease cases, and there are a number of familial cases that are not linked to any of the four genes. This suggests that important genetic factors have yet to be identified. The key events in Alzheimer's disease are cytoskeletal changes and the formation of paired helical filaments, and these are common to the two hallmarks of Alzheimer's disease: neuritic plaques and neurofibrillary tangles. So far there is no explanation as to how the identified genes cause these events. Here we speculate that paired helical filaments can form as a result of overexpression of the DSCR1 (Adap78) gene. b Amyloids and/or other stress factors can induce DSCR1 (Adap78) and cause decreased activity of calcineurin. Chronic downregulation of calcineurin can lead to gradual accumulation of hyperphosphorylated tau, the formation of paired helical filaments and Alzheimer's disease-like cytoskeletal changes.
Ermak
Gennady
G
Ethel Percy Andrus Gerontology Center and Division of Molecular & Computational Biology, The University of Southern California, Los Angeles 90089-0191, USA. kelvin@usc.edu
Davies
Kelvin J A
KJ
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000031:analogs & derivatives* / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D053764:Presenilin-1; D053766:Presenilin-2
C489697:APLP1 protein, human; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2