Next-generation mouse models of Alzheimer’s disease

December, 2015: The number of collaborations using the next-generation mouse models of Alzheimer’s disease exceeded 130! It took us only a year and half to reach this number since the publication of our Nature Neuroscience paper in April 2014. Achievements obtained using these model mice will be reported from all over the world in 2015 and after.

The 1st generation (conventional) mouse models that have been generated since 1995 suffer from the following intrinsic problems because they highly overexpress amyloid precursor protein (APP). Please see the Western blot data of Tg2576 mice. PD-APP mice appear even worse (Games et al, Nature, 1995). Please see the Western blot data of PD-APP mice. We estimate approximately 60% of the results published thus far to be artifacts.

  1. Overexpression of membrane proteins such as APP and presenilin induce ER stresses leading to a number of cellular responses, such as transcriptional suppression, UPR, IP3 receptor activation, etc. IP3 receptor activation will elevate intracellular calcium and may consequently cause epilepsy.
  2. APP overexpression perturbs axonal transport because APP interacts with kinesin via JIP-1.
  3. Not only Aβ but also other APP fragments such as sAPP, CTF-β, CTF-α and AICD are overproduced. These fragments may possess some biological functions.
  4. Cross-breeding APP-Tg mice with other mutant mice is likely to generate even more-complicated artifacts.
  5. Cell type-specific alternative splicing of APP mRNA is spared.
  6. Utilization of artificial promoters results in transgene expression in cells not necessarily identical to those expressing endogenous APP.
  7. Artificial promoters may compete with endogenous promoters for common transcription factors.
  8. The transgene is inserted into a gene locus of the host animal, often in a multi-copy manner, and destroys endogenous gene(s). Two loci are destroyed in double Tg mice that overexpress mutant APP and presenilin 1.
  9. Expression of the transgene varies from line to line and from time to time.
  10. Mouse lines to be used are generally selected in a phenotype-biased manner.
  11. APP-Tg mice often die of unknown cause(s).

To overcome these drawbacks, we spent 12 years to generate knockin mice that harbor Swedish and Beyreuther/Iberian mutations in the APP gene, and demonstrated that these animals start accumulating Aβ at 6 months and show memory impairment at 18 months without APP overexpression. We also generated mice containing an additional Arctic mutation; these started depositing Aβ at 2 months and showed memory impairment at 6 months with aggressive neuroinflammation. This work was published in Nature Neuroscience in April of 2014. The models already being used by almost 100 top scientists (see a list of some) in the world are becoming gold standard models of Alzheimer’s disease. They will contribute to development of diagnosis, prevention and therapy for Alzheimer’s disease without exhibiting artificial phenotypes. Please see the introduction at RIKEN homepage. The AlzForum Webinar also discusses the value of new mouse models.

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Neuroinflammation in our mouse model of AD