Audrain M, Souchet B, Alves S, Fol R, Viode A, Haddjeri A, Tada S, Orefice NS, Joséphine C, Bemelmans AP, Delzescaux T, Déglon N, Hantraye P, Akwa Y, Becher F, Billard JM, Potier B, Dutar P, Cartier N, Braudeau J. βAPP Processing Drives Gradual Tau Pathology in an Age-Dependent Amyloid Rat Model of Alzheimer's Disease. Cereb Cortex. 2017 Oct 18;:1-18. PubMed.
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In the AAV-AD rat model, the majority of the hippocampal cells have no genetic modification, making it a relevant model for the non-genetic forms of the disease that represent more than 92 percent of cases (Prince et al., 2015). Indeed, the technology used is not based on a transgenic approach. Because disease induction is conducted only on adult animals, AAV-AD rats do not suffer from developmental compensation or genetic drift.
Moreover, the pattern of APP expression in AAV-AD model may mimic both genomic mosaicism and APP gene recombination recently described in the sporadic form of human AD, in which an increase in copy number was observed for the APP gene in a limited subset of neurons (Bushman et al., 2015) and an appearance of somatic mutations known to be associated with familial form of Alzheimer’s disease was described (Lee et al., 2018). The AAV-AD rat model could thus be considered as a closer model of the sporadic form of AD than transgenic animals.
Its pathophysiological relevance has been validated by comparing it to postmortem samples of AD patients. The concentration of Aβ42 peptide gradually increases to reach, at the late stage, concentrations comparable to those measured in the hippocampi of AD patients. As hyperphosphorylation of the endogenous tau protein gradually takes place, the memory capacity simultaneously declines, reproducing the chronology of events progression seen in clinics. Amyloid plaques and cerebral amyloid angiopathy develop only in aged AAV-AD rats. Intraneuronal aggregates of hyperphosphorylated tau protein confirm a full commitment of the tau pathology (Audrain et al., 2017).
All these features make the AAV-AD rat model a powerful tool to better predict the preventive drug efficacy during clinical trials. It could thus accelerate the development of therapies, specifically acting during silent AD phases, for secondary prevention. This model also constitutes a study system to characterize new biomarkers or panels of biomarkers of early diagnosis, disease progression, target engagement, and drug efficacy.
References:
Bushman DM, Kaeser GE, Siddoway B, Westra JW, Rivera RR, Rehen SK, Yung YC, Chun J. Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer's disease brains. Elife. 2015 Feb 4;4 PubMed.
Audrain M, Souchet B, Alves S, Fol R, Viode A, Haddjeri A, Tada S, Orefice NS, Joséphine C, Bemelmans AP, Delzescaux T, Déglon N, Hantraye P, Akwa Y, Becher F, Billard JM, Potier B, Dutar P, Cartier N, Braudeau J. βAPP Processing Drives Gradual Tau Pathology in an Age-Dependent Amyloid Rat Model of Alzheimer's Disease. Cereb Cortex. 2017 Oct 18;:1-18. PubMed.
Lee MH, Siddoway B, Kaeser GE, Segota I, Rivera R, Romanow WJ, Liu CS, Park C, Kennedy G, Long T, Chun J. Somatic APP gene recombination in Alzheimer's disease and normal neurons. Nature. 2018 Nov;563(7733):639-645. Epub 2018 Nov 21 PubMed.
Prince M, Wimo A, Guerchet M, Ali GC, Wu YT, Prina M. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. World Alzheimer Report 2015, Alzheimer’s Disease International, London.
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