Takaomi Saido

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Takaomi Saido

  1. 1. Greetings: RIKEN BSI Proteolytic Neuroscience Laboratory BSI Central Building, April 17, 2014.
  2. 2. Takaomi C. Saido Laboratory for Proteolytic Neuroscience RIKEN Brain Science Institute JAPAN Alzforum Webiner April 22, 2014 2nd generation mouse models of Alzheimer’s disease: 12 years of work and future perspectives
  3. 3. Crossing Tg mice overexpressing mutant APP with other Tg mice is a risky paradigm. Example: APP-Tg X Calpastatin- Tg/KO.
  4. 4. 0 20 40 60 80 100 0 10 20 30 40 50 60 Age (weeks) Proportionsurviving(%) WT CS-KO APP/CS-Tg APP-TgAPP-Tg CS-KO (+/-) APP-Tg CS-KO (-/-) Effect of calpastatin (CS) overexpression & deficiency on life span of APP-Tg mice Higuchi et al. FASEB J. (2012
  5. 5. 2nd generation KI mouse model of A amyloidosis:β APPNL-F β-cleavage site γ-cleavage site 671 Aβ42Aβ40 R Y H humanization Aβ:3-fold NL SEVKM DAEFGHDSGFEVRHQKLVFFAEDVGSNKGAIIGLMVGGVV IA TVIVITLVMLK 670 Overproduction of Aβ1-42 Aβ42/Aβ40 ratio: 30-fold F Beyreuther/Iberian mutation Saito et al. (Nat Neurosci, 2014 Overproduction of APPsβ NL-F Relevant negative control?
  6. 6. negative control for the 2nd generation KI mouse model: APPN β-cleavage site γ-cleavage site 671 Aβ42Aβ40 R Y H humanization Aβ:3-fold NL SEVKM DAEFGHDSGFEVRHQKLVFFAEDVGSNKGAIIGLMVGGVV IA TVIVITLVMLK 670 Overproduction of Aβ1-40/42 Saito et al. (Nat Neurosci, 2014 Age of onset: 50-60 years Overproduction of APPsβ NL Relevant negative control!
  7. 7. 500 µm Amyloidburden(%) HippocampusCortex 4G8 15 mo 18 mo12 mo9 mo 21 mo 24 mo Age-dependent Aβ deposition in NL-F/NL-F Aβ deposition could be detected from 6 mo of NL-F/NL-F brains
  8. 8. APP KICS-KO CS-KO; APP KI Modulation of calpain activity in APP-KI mouse brain by crossbreeding with Calpastatin (CS)-KO mice New!
  9. 9. Survival of APPNL/F -KI x Calpastatin (CS)-KO mice CS deficiency did not affect the survival of APPNL-F KI mice at least up to 20 months.
  10. 10. 1. Role of inflammation 2. Role of various proteases 3. Effect of Aβ vaccination 4. Effect of ApoE4 5. Effect of the environmental enrichment 6. Effect of various diets and supplements 7. Others (Tau, Dynamin, Arc, etc.) Major issues to be re-addressed
  11. 11. 3rd generation KI mouse model of A amyloidosis: APPβ NL-G-F β-cleavage site γ-cleavage site 671 Aβ42Aβ40 R Y H humanization NL SEVKM DAEFGHDSGFEVRHQKLVFFAEDVGSNKGAIIGLMVGGVV IA TVIVITLVMLK 670 F Beyreuther/Iberian mutation Saito et al. (Nat Neurosci, 2014 SEVNL DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV IA TVFVITLVMLK G (Arctic mutation) Oligomerization-prone NL-G-F
  12. 12. 500 µm 2 months 4 months 7 months Aβ42 pathology of NL-G-F KI mice
  13. 13. Neuroinflammation in APPNL-G-F/NL-G-F KI Greater neuroinflammation was found around the plaques in APPNL-G-F/NL-G-F mice than aged APPNL-F/NL-F KI mice. APPNL-F/NL-F (24 mo) APPNL-G-F/NL-G-F (9 mo) Aβ(82E1) microglia astrocyte merge
  14. 14. Differential utility of NL-F and NL-G-F mice 1. NL-F: Mechanism of Aβ deposition (up-stream targets). 2. NL-G-F: Mechanism of inflammation, tauopathy and neurodegeneration (down-stream targets).
  15. 15. Finally, we should compare our mice with APPNL/NL mice crossbred with mutant presenilin 1 (PS1) knockin mice24 , which also overproduce Aβ42 without overexpressing APP. These APP/PS1 double knockin mice are comparable to the APPNL-F/NL-F mice in this respect. There are, however, two major difficulties that limit the utility of the double knockin mice. The first is that they are doubly homozygous: crossing them with other mutant mice is practically impossible. To our knowledge, no researchers have done so as yet. The second is that presenilin mutations affect biological processes other than γ-cleavage of APP25 ; no perfect negative controls exist. It should also be noted that the function(s) of PS1 may, at least in part, differ between humans and mice26 .
  16. 16. RIKEN BSI   Lab. for Proteolytic Neuroscience Takashi Saito Nobuhisa Iwata (Nagasaki U) Makoto Higuchi (NIR) Jiro Takano Satoshi Tsubuki Per Nilsson Naomasa Kakiya Kaori Tsukakoshi Hayato Isshiki Ko Sato Shoko Hashimoto Contributors and Collaborators RIKEN BSI Lab. for Behavioral Genetics   Shigeyoshi ItoharaNational Institute for Geriatrics and Gerontology Akihiko Takashima University of Minnesota Karen Hsiao-Ashe Novartis Institute of Medical Research Matthias Staufenbiel Jichi Medical University Shin-ichi Muramatsu Harvard Medical School Cynthia Lemere

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