The effect of presenilin-1 on cerebral amyloid protein

• Project/Area Number: 09835024
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 老化(加齢)
• Research Institution: Osaka City University Medical School (1998); Tokyo Institute of Psychiatry (1997)
• Principal Investigator: MORI Hiroshi Medical School, Osaka City University, Professor, 医学部, 教授 (10159189)
• Co-Investigator(Kenkyū-buntansha): SAHARA Nobuhiko Medical School, Osaka City University, Research Associate, 医学部, 助手 (40261185) ; 宇佐美 美穂子 (財)東京都精神医学総合研究所, 技術部, 研究員 (10261182)
• Project Period (FY): 1997 – 1998
• Project Status: Completed (Fiscal Year 1998)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 1998: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 1997: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: Alzheimer's disease / presenilin-1 / mutation / senile plague / amyloid / プレセニリン-1 / 家族性アルツハイマー病 / アミロイド蛋白

Research Abstract

The effect of presenilin-1 on cerebral amyloid b protein
Amyloid beta protein (Abeta) in senile plaque and amyloid angiopathy is important not only for neuropathological hallmarker but also for the causal gene (APP) product. The possible interaction of APP and presenilin-1, another causal gene localized on chromosome 14, becomes the crutial issue for the etiology of the disease. Here we analyzed the effect of presenilin-1 on cerebral Abeta deposition in patients with Alheimer's disease.
Abeta is composed of Abeta1-4O and Abeta1-42/43. Accumulating evidence shows that the causal mutation of presenilin-1 induces the higher concentration of Abeta1-42/43 than Abeta1-40. However, the present analysis showed also that the mutation causes significantly higher Abeta1-40 in addition to Abeta1-42/43 in AD patients. This may be related with the recent findings on multiple function for presenilm-1 that (1) presenhlin-1 null mice show both defects on Abeta1 production and developmental segmentation, (2) presenilin-1 could bind APP, beta-catenin and GSK3beta molecules. Thus, it is highly likely that presenilin-l affect both Abeta species. This remains to be studied using transgenic mouse model in future.

Research Products

• [Publications] Zhang,J.,Kang,D.E.,Xia,W.Okochi,M.,Mori,H.,Selkoe,DJ.,& Koo,EH.: "Subcellular distribution and turnover of presenilins in transfected cells" J.Biol.Chem.273. 12436-12442 (1998)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tamaoka A,Fraser PE,Ishii K,Sahara N,Ozawa K,Ikeda K,Saunders AM,Komatsuzaki Y,Sherrington R,Levesque G,Yu G,Rogaeva E,Shoji S,NeeL.E.,Pollen DA,Hendriks L,Martini JJ,Van Broeckhorenh C,Roses AD,Farrerj LA,St.George-Hyslop PH,and Mori H.: "Amyloid-β-protein isoforms in brain of subjects with PS1-linked,βAPP-linked and sporadic Alzheimer's disease" Mol.Brain Res.56. 178-185 (1998)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Lippa CF,NeeLE,Mori H,and George-Hyslop P: "Aβ-42 deposition precedes other changes in PS-1 Alzheimer's disease" The Lancet. 352. 1117-1118 (1998)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Arai T,Ikeda K,Akiyama H,Haga C,Usami M,Sahara N,Iritani S,and Mori H.: "A high incidence of apolipoprotein Ee4 allele in middle-aged non-demented subjects with cerebral amyloid β protein deposits" Acta Neuropathol.97. 82-84 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Arawaka S,Usami M,Sahara N,Schellenberg GD,Lee G,& Mori H.: "The tau mutation (val337met) disrupts cytoskeletal networks of microtubules (in press)" Neuro Report. (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Zhang, J., Kang, D.E., Xia, W., Okochi, M., Mori, H., Selkoe, D.J., & Koo, E.H.: "Subcellular distribution and turnover of presenilins in transfected cells." J.Biol.Chem.273. 12436-12442 (1998)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tamaoka, A., Fraser, P.E., Ishii, K., Sahara, N., Ozawa, K., Ikeda, K., Saurders, A.M., Komatsuzaki, Y., Sherrington, R., Levesque, G., Yu, G., Rogaeva, E., Shoji, S., Nee. L.E., Pollen, D.A., Handriks, L., Martini, J.J., Van Broeckhovenh, C., Roses, A.D., Farrerj, L.A., St.George-Hyslop, P.H., and Mori, H.: "Amyloid-beta-protien isoforms in brain of subjects with PS1-linked, betaAPP-linked and sporadic Alzheimer's disease" Mol.Brain Res. 56. 178-185 (1998)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Lippa, C.F., Nee, L.E., Mori, H., and George-Hyslop, P.: "Abeta-42 deposition precedes other changes in PS-1 Alzheimer's disease" The Lancet. 352. 1117-1118 (1998)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Arai, T., Ikeda, K., Akiyama, H., Haga, C., Usami, M., Sahara, N., Iritani, S., and Mori, H.: "A high incidence of a polipoprotein Ee4 allele in middle aged non-demented subjects with cerebral amyloid beta protein deposits" Acta Neuropathol.97. 82-84 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Arawaka, S., Usami, M., Sahara, N., Schellenberg, G.D., Lee, G., & Mori, H.: "The tau mutation (val 337 met) disrupts cytoskeletal networks of microtubules" Neuro Report. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Zhang J,Kang DE,Xia W,Okochi M,Mori H,Selkoe DJ,& Koo EH: "Subcellular distribution and turnover of presenilins in transfected cells" J.Biol.Chem.273. 12436-12442 (1998)
• [Publications] Tamaoka A,Fraser PE,Ishii K,Sahara N,Ozawa K,Ikeda K,Saunders AM,Komatsuzaki Y,Sherrington R,Levesque G,Yu G,Rogaeva E,Shoji S,Nee LE,Pollen DA,Hendriks L,Martini JJ,Van Brocckhoveah C,Roses AD,Farrerj LA,St.George-Hyslop PH,and Mori H: "Amyloid-β-protein isoforms in brain of subjects with PS1-linked,BAPP-linked and sporadic Alzheimer's disease" Mol.Brain Res.56. 178-185 (1998)
• [Publications] Lippa CF,Nee LE,Mori H,& George-Hyslop P: "Aβ-42 deposition precedes other changes in PS-1 Alzheimer's disease" The Lancet. 352. 1117-1118 (1998)
• [Publications] Arai T,Ikeda K,Akiyama H,Haga C,Usami M,Sahara N,Iritani S and Mori H: "A high incidence of apolipoprotein Ee4 allele in middle-aged non-demented subjects with cerebral amyloid β protein deposits" Acta Neuropathol.97. 82-84 (1999)
• [Publications] Arawaka S,Usami M,Sahara N,Schellenberg GD,Lee G,& Mori H.: "The tau mutation(val 337 met)disrupts cytoskeletal networks of microtubules" Neuro Report. in press. (1999)
• [Publications] ISHii,K.,Tamaoka,A.,Mizusawa,H.et al.: "Aβ1-40 but not Aβ1-42 levels in cortex correlate with apolipoprotein E e4 allele dosage in sporadic Alzheimer's disease" Brain Res.748. 250-252 (1997)
• [Publications] Ishii,K.,li,K.,Hasegawa,T.et al.: "Increased Aβ42(43)-plaque deposition in early-onset familial Alzheimer's disease brains with the deletion of exon 9 and the missense point mutation(H163R)in the PS-1 gene" Neurosci.Lett.228. 17-20 (1997)
• [Publications] Sawamura,N., Tamaoka, A.,Shoji,S.-l.et al.: "Characterization of amyloid β protein species in cerebral amyloid angiopathy of a cynomolgous monkey by immunocytochemistry and enzyme-linked immunosorbent assay" Brain Res. 764. 225-229 (1997)
• [Publications] Okochi,M.,Ishii,K.,Usami,M.et al.: "Proteolytic processing of presenilin-1(PS-1)is not associated with Alzheimer's disease with or without PS-1 mutations" FEBS Lett.418. 162-166 (1997)
• [Publications] Yamamoto,A., Takagi,H.,Kitamura,D.et al.: "Deficiency in Protein L-isoaspartyl Methyltransferase Results in a Fatal Progressive Epilepsy" J.Neurosci.(in press). (1997)
• [Publications] Tamaoka,A.,Fraser,P.E.,Ishii,K.et al.: "Amyloid-β-protein isoforms in brain of subjects with PS1-linked,βAPP-linked and sporadic Alzheimer's disease" Mol.Brain Res.(in press). (1998)