A presentation by:

Alzheimer’s Disease

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

Basic Concepts / Principles

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Strategies of Knock-in Technology●

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Generation of Knock-in Mouse Model

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● 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)

Conclusion

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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.