Can Alzheimer’s-in-a-dish models accelerate AD drug discovery?
by Rudolph Tanzi, Ph.D. on 8 April 2016
Alzheimer’s disease (AD) transgenic mice have been used as a standard model for AD drug discovery and basic mechanistic studies. These mouse models overexpress amyloid β precursor protein (APP) or APP/presenilin (PS) with single or multiple familial AD (FAD) mutations, which lead to excess accumulation of amyloid β (Aβ), a well-known driver for AD pathogenesis. These mice exhibit several symbolic features of AD including Aβ-induced synaptic/memory deficits and Aβ aggregation (Aβ plaque), which have been proven very useful for testing candidate AD drugs before human trials. However, they have not been able to fully replicate key AD pathogenic cascades including clear tau tangle pathology and neurodegeneration, which might explain why many successful treatments in mice did not lead to similar success in humans.
The failure to fully recapitulate AD pathologies in mice challenges the reigning Aβ hypothesis, which predicts that accumulation of excess pathogenic Aβ leads to neurofibrillary tangles and eventual neurodegeneration. However, the shortcomings of current mouse models based on FAD mutations may possibly be due to fundamental species-specific differences. Indeed, adult mice do not express the six human tau isoforms essential for recapitulating tau tangle pathology, and furthermore, endogenous mouse tau proteins seem to interfere with the aggregation of human tau [1,2].
The problems that may rise from species-specific differences can be easily solved in human models. Induced pluripotent stem cell (iPSC) technology has provided a new model system to recapitulate AD pathogenesis in human neuronal environments. iPSC-derived human neurons have been generated from the fibroblasts of AD patients, including those with APP or PS FAD mutations [3-11]. As predicted, these FAD neurons showed significant increases in pathogenic Aβ species and interestingly, some of them showed accumulation of hyperphosphorylated tau, be an early signal of developing tau tangle pathology. However, these cellular models have been unsuccessful in demonstrating robust Aβ plaques, tau tangles, and neurodegeneration.
Recently, we developed a novel 3D human neural culture model that produces robust Aβ plaques and tau tangles [12,13]. As in AD mouse transgenic models, we overexpressed APP and PS1 with FAD mutations in immortalized human neural progenitor cells and differentiated them into neurons and astrocytes in 3D Matrigel culture conditions. We found that this 3D system dramatically accelerated the aggregation of pathogenic Aβ species (Aβ plaques) and more excitingly, induced accumulation of silver-positive, detergent-insoluble hyperphosphorylated tau protein, which clearly indicates the presence of tau tangles. Using this model, we were also able to show that blocking Aβ generation dramatically decreased hyperphosphorylated tau accumulation, which supports the current Aβ hypothesis.
These exciting new human cellular AD models offer faster, cheaper high-throughput screening platforms for novel AD drug discovery in comparison to current transgenic mouse models. While AD iPSC-derived models could be used for testing candidate drugs that intervene in early-stage AD pathogenesis, our 3D culture model may a good fit for discovering drugs that block later points in pathogenic cascades, such as accumulation/aggregation of Αβ and hyperphosphorylated tau. AD transgenic mouse models could subsequently be used to re-confirm drug targets identified in the cellular models. In addition to drug screening, human cellular AD models can be used to explore AD pathogenic mechanisms in human neuronal cells, which might provide additional targets for AD drug discovery.
The exciting new array of cellular models may be the keys we need to unlock the mysteries of AD pathogenesis, but we must strive to optimize our current models and continue to create new ones. Until now, the cellular AD models have not been able to precisely reconstitute the brain regions most affected in AD: the hippocampus and cortical layers. Recent progress in generation of organoid systems holds much promise . Additionally, iPSC and our 3D culture model may have captured a significant part of AD pathogenesis, but we still have yet to show the clear neurodegeneration seen in brains of AD patients. Better understanding of the role microglial cells play in AD pathogenesis will be essential for the development of human cellular models that reconstitute robust neuronal death stemming from Aβ and tau pathologies. These integrated neuroinflammatory models will be crucial for movement towards better a mechanistic understanding of AD pathology, and development of effective therapeutics.
Currently, AD affects 5.3 million individuals in the US and that number is expected to increase dramatically over the next decade. We are cautiously optimistic that these new cellular AD models can accelerate discovery of new AD drugs and also enable dissection of molecular mechanisms underlying the pathogenic cascades of AD.
Doo Yeon Kim, PhD, Jenna Aronson, and Rudolph E. Tanzi, PhD
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Last comment on 8 April 2016 by Christopher Navara