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Leveraging preclinical models for the development of Alzheimer disease therapeutics

Nature Reviews Drug Discovery volume 19, pages 447–462 (2020)Cite this article

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Abstract

A large number of mouse models have been engineered, characterized and used to advance biomedical research in Alzheimer disease (AD). Early models simply damaged the rodent brain through toxins or lesions. Later, the spread of genetic engineering technology enabled investigators to develop models of familial AD by overexpressing human genes such as those encoding amyloid precursor protein (APP) or presenilins (PSEN1 or PSEN2) carrying mutations linked to early-onset AD. Recently, more complex models have sought to explore the impact of multiple genetic risk factors in the context of different biological challenges. Although none of these models has proven to be a fully faithful reproduction of the human disease, models remain essential as tools to improve our understanding of AD biology, conduct thorough pharmacokinetic and pharmacodynamic analyses, discover translatable biomarkers and evaluate specific therapeutic approaches. To realize the full potential of animal models as new technologies and knowledge become available, it is critical to define an optimal strategy for their use. Here, we review progress and challenges in the use of AD mouse models, highlight emerging scientific innovations in model development, and introduce a conceptual framework for use of preclinical models for therapeutic development.

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Fig. 1: Mechanisms of pathogenesis in Alzheimer disease.
Fig. 2: Timeline outlining the discovery of Alzheimer disease genetic risk factors.
Fig. 3: Proposed framework to increase translational predictability of animal models for AD.
Fig. 4: Strategy to discover and develop translatable biomarkers using animal models.

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Acknowledgements

The authors thank R. J. Watts and G. Di Paolo for critical discussion and input, N. Effenberger for administrative assistance in preparing the manuscript and M. Larhammar for graphic design.

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  1. These authors contributed equally: Kimberly Scearce-Levie, Pascal E. Sanchez, Joseph W. Lewcock.

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Related links

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MODEL-AD: https://www.model-ad.org/

Glossary

Gliosis

Proliferation, migration and morphological changes of glial cells in response to injuries to the central nervous system.

Neurofibrillary tangles

Pathological aggregates containing tau, most commonly observed in Alzheimer disease and frontotemporal dementia.

Lewy bodies

Pathological aggregates containing α-synuclein, most commonly observed in Parkinson’s disease and Lewy body dementia.

Water maze test of cognition

Behavioural test to evaluate spatial learning and memory; using visual cues, mice learn to locate and swim to a submerged and hidden platform in a pool.

Cellular potency

Level of bioactivity of a compound on specific cellular function.

Hybrid strains

Strains generated by crossing mice from a distinct genetic background.

Inbred strains

Strains generated by crossing mice from an identical genetic background.

MODEL-AD initiative

Consortium funded by the US National Institute on Aging to develop and evaluate mouse models for late-onset Alzheimer disease.

Floxed alleles

DNA construct in which a gene is flanked by loxP sites, enabling deletion, translocation, insertion or inversion of this gene.

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Scearce-Levie, K., Sanchez, P.E. & Lewcock, J.W. Leveraging preclinical models for the development of Alzheimer disease therapeutics. Nat Rev Drug Discov 19, 447–462 (2020). https://doi.org/10.1038/s41573-020-0065-9

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