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Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder that leads to a progressive decline in a person’s memory and ability to communicate and carry out daily activities. The brain pathology in AD is characterized by extensive neuronal loss, particularly of cholinergic neurons, intracellular neurofibrillary tangles composed of the tau protein (NFTs) and extracellular deposition of plaques composed of β-amyloid (Aβ), a cleavage product of the amyloid precursor protein (APP). These two insoluble protein aggregates are accompanied by a chronic inflammatory response and extensive oxidative damage. Whereas dys-regulation of APP expression or processing appears to be important for the familial, early-onset form of AD, controversy exists between the “Baptists” (in favour of Aβ) and the “Tauists” (in favour of tau) as to which of these two protein dysfunctions occur at the earliest stages or are the most important contributors to the disease process in sporadic AD. However, more and more “non-amyloid” and “non-tau” causes have been proposed, including, glycation, inflammation, oxidative stress and dys-regulation of the cell cycle. However, to get an insight into the ultimate cause of AD, and to prove that any drug target is valuable in AD, disease-relevant models giving insight into the pathogenic processes in AD are urgently needed. In the absence of a good animal model for sporadic AD, we propose in this review that induced pluripotent stem cells, derived from dermal fibroblasts of AD patients, and differentiated into cholinergic neurons, might be a promising novel tool for disease modelling and drug discovery for the sporadic form of AD.

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Acknowledgments

We thank Peter Riederer for his brilliant scientific ideas and valuable mentorship in his long and distinguished scientific career. We gratefully acknowledge the grant support of the National Health and Medical Research Council (Grant IDs: 436797, 606543, 1046227) and Alzheimer’s Australia.

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, University of Western Sydney, Locked Bag 1797, Penrith South DC, 1797, Australia

    Lezanne Ooi & Gerald Münch

  2. Bioanalytical Mass Spectrometry Facility, University of New South Wales, Kensington, Australia

    Anne Poljak

  3. Regenerative Medicine, School of Medicine, University of Western Sydney, Campbelltown, Australia

    Michael D. O’Connor

  4. Molecular Medicine Research Group, University of Western Sydney, Campbelltown, Australia

    Michael D. O’Connor & Gerald Münch

  5. Brain and Ageing Research Program, School of Psychiatry, University of New South Wales, Sydney, Australia

    Perminder Sachdev

  6. Stem Cell Laboratory, Faculty of Medicine, University of New South Wales, Sydney, Australia

    Kuldip Sidhu

  7. Discipline of Pathology, School of Medical Sciences, University of Sydney, Sydney, NSW, 2006, Australia

    Greg Sutherland

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  1. Lezanne Ooi
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  2. Kuldip Sidhu
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  7. Gerald Münch
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Correspondence to Gerald Münch.

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Ooi, L., Sidhu, K., Poljak, A. et al. Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease. J Neural Transm 120, 103–111 (2013). https://doi.org/10.1007/s00702-012-0839-2

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