[Understanding of molecular pathogenesis of Alzheimer's disease: implications for drug development].
Recent advances in the knowledge about Alzheimer pathogenesis indicate several tactics for the development of drugs to treat Alzheimer's disease. Firstly, the function of presenilin, the causative gene for most familial Alzheimer's disease, has been demonstrated to be the protease in the Notch signaling system. Presenilin cleaves the transmembrane domain of the C-terminal fragment of the Notch-1 molecule, which is generated by proteolysis by furin-like proteases. APP is also cleaved by presenilin at the gamma cut site, implying that presenilin is gamma-secretase itself or at least closely functioning with gamma-secretase. A recent paper has demonstrated that immunization of APP transgenic mouse with amyloid beta 42 may decrease and prevent amyloid deposition in brain tissue. This unique and novel approach may open the new tactics for developing anti-dementia drugs. Another important finding comes from the identification of the function of prolyl isomerase. It is demonstrated that pin 1, intra-nuclear prolyl isomerase, can restore the microtubule binding capacity of phosphorylated tau, which clearly shows a solid strategy for developing drugs for preventing neuronal degeneration.
Takeda
M
M
Department of Clinical Neuroscience, Osaka University Graduate School of Medicine, Japan.
Shinosaki
K
K
Nishikawa
T
T
Tanaka
T
T
Kudo
T
T
Nakamura
Y
Y
Kashiwagi
Y
Y
D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000628:therapy; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D009410:Nerve Degeneration; D019696:Peptidylprolyl Isomerase / Q000502:physiology / Q000627:therapeutic use; D010766:Phosphorylation; D053764:Presenilin-1; D053766:Presenilin-2; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D016875:tau Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D016875:tau Proteins; D019696:Peptidylprolyl Isomerase