Alzheimer’s Disease
What happens in the brain?
Amyloid Precursor Protein (APP)
β-amyloid peptide
(Hall & Roberson 2012)
Early onset Alzheimer’s
➤ Single gene mutations on:
➭ chromosome 21 → abnormal APP
➭ chromosome 14 → abnormal presenilin 1
➭ chromosome 1 → abnormal presenilin 2
➤ ↓ activity of -secretase (an enzyme important in βAP formation)
Late onset Alzheimer’s
➤ Due to apolipoprotein E (apoE) gene on chromosome 19
➤ Different isoforms of apoE:
apoE2 , apoE3 , apoE4
➤ Inheritance of apoE4 (risk-factor gene) allele ↑ the risk
➤ Degree of risk depends on:
Number of copies of apoE gene , Age, Ethnicity
● murine Aβ sequence was humanized by changing three amino acids that differ between mice and humans and introduce FAD mutations into the endogenous mouse App gene.
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(Sasaguri et al. 2017)
How to generate knock-in Alzheimer’s mouse?
3 types of App knock-in mice
● Based on different combinations of mutations
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NLNL-FNL-G-F
(Masuda et al. 2016)
Applications / Implications for Alzheimer’s Disease
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○ (eg. via cross breeding with appropriate mutant mice)
●(Sasaguri et al. 2017)
Current Development / Challenges
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(Sasaguri et al. 2017)
Figure 6: An excerpt from an article by Christian Matheou (Matheou 2017)
References
Hall, A, & Roberson, E 2012, ‘Mouse models of Alzheimer's disease’, Brain Research Bulletin, vol.88, no.1, pp. 3-12, viewed 20 Oct. 2017, <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546481/>.
Masuda, A, Kobayashi, Y, Kogo, N, Saito, T, Saido, TC, Itohara, S 2016, ‘Cognitive deficits in single App knock-in mouse models’, Neurobiology of Learning and Memory, vol. 135, pp. 73-82.
Mouse models, tau tangles and neurodegeneration in Alzheimer’s disease, BioMed Central, viewed 20 October 2017, <https://blogs.biomedcentral.com/on-biology/2017/01/03/mouse-models-tau-tangles-neurodegeneration-alzheimers-disease/>.
References
APP mouse models for Alzheimer's disease preclinical studies’, The EMBO Journal, vol.36, no.17, pp. 2473-2487.
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