Rodent Models of Amyloid-Beta Feature of Alzheimer’s Disease: Development and Potential Treatment Implications

The article in 3 sentences.

  1. Existing animal models of Abeta overexpression are inadequate in mimicking the full spectrum of clinicopathological characteristics of Alzheimer’s disease.
  2. The lack of a comprehensive disease model has hindered the translation of apparent therapeutic effects exerted by experimental drugs from the lab bench to the bedside.
  3. A multitude of other pathogenic pathways has been postulated to precede Alzheimer’s disease: neuroinflammation, neurotrophic factors, neuroplasticity, neurogenesis, mitochondrial dysfunction, and neurotransmitter dysfunction. Animal models for these pathogenic cascades are required to further our understanding of Alzheimer’s disease.

The 5XFAD rodent model encompasses all 3 mutations which are located on human APP751. The photomicrographs show intense amyloid plaque formation in various brain regions.

How has the article changed my thinking?

  1. The pathogenesis of Alzheimer’s disease is not as linear as I thought. The amyloid cascade hypothesis certainly is nowhere near the complete picture. It could be one of the causes of AD, leading to downstream neuroinflammation, bioenergy generation, and neuronal death. But more plausibly, based on the broad array of mechanistic pathologies presented in this article, amyloid could very well be a consequence of another initial insult. A potentiator of disease progression, no doubt, but merely one piece of the bigger puzzle. This knowledge gap is interestingly demonstrated by the fact that 9-month-old Tg6590 rats showed impaired spatial learning and memory in the MWM and reduced exploratory behaviors in the Open Field Test (OFT), which manifested prior to Aβ deposition [1].
  2. The ambiguous benefits of anti-Abeta treatments in clinical trials are a clear signal that we have to go back to the drawing board when it comes down to formulating AD treatment. It is about time that we re-examine the molecular basis and animal models that have such deep roots within our thinking. Rather than utilizing existing medications and trying to throw them against the wall and see what sticks, we must be particular about what we know and don’t know about the disease and the brain’s circuitry. I believe this should begin with familial AD as the epitome of the disease entity, given the seemingly straightforward pathogenesis cascade—which we have yet to uncover. The fact that overexpression of FAD-related APP mutations is not sufficient to completely micmic human AD suggests that there is something that we are mission.
  3. Future directions of research should be aimed at earlier pathologies, even before amyloid plaques have been formed. This, of course, is a tremendous feat in itself, as how are we supposed to know what happens before what we can measure happens (cognitive impairment, amyloid plaques)? This is where animal models come into play, whereby we are certain that they will develop AD, as in familial AD models. Through longitudinally studying their brain circuitry, we can perhaps isolate initial events leading to the symptoms ultimately.

What are some related / contradicting ideas?

  1. An article illustrating the interplay between mitochondrial dysfunction and neurotransmitter dysfunction. The authors appear to signify a vicious cycle between the various stakeholder molecules in which the initiation event is far from clear.

Further reading:

  1. Kloskowska E, Pham TM, Nilsson T, Zhu S, Oberg J, Codita A, et al. (2010). Cognitive impairment in the Tg6590 transgenic rat model of Alzheimer’s disease. J Cell Mol Med, 14:1816-1823.
  2. Kummer MP, Hammerschmidt T, Martinez A, Terwel D, Eichele G, Witten A, et al. (2014). Ear2 deletion causes early memory and learning deficits in APP/PS1 mice. J Neurosci, 34:8845-8854.
  3. Herzog CD, Bishop KM, Brown L, Wilson A, Kordower JH, Bartus RT (2011). Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases. Drug Deliv Transl Res, 1:361-382.
  4. Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, et al. (2005). A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med, 11:551-555.
  5. Ferreira D, Westman E, Eyjolfsdottir H, Almqvist P, Lind G, Linderoth B, et al. (2015). Brain changes in Alzheimer’s disease patients with implanted encapsulated cells releasing nerve growth factor. J Alzheimers Dis, 43:1059-1072.

References

  • Author: Chi Him Poon, Lee Wei Lim
  • Original text: click here