Multi-Loop Model of Alzheimer
Disease: An Integrated Perspective
on the Wnt/GSK3β, α-Synuclein,
and Type 3 Diabetes Hypotheses
A review on the Wnt/Glycogen Synthase Kinase 3β (GSK3β), α-synuclein, and type 3 diabetes hypotheses of Alzheimer disease and their deep interconnection.
As the prevalence of Alzheimer disease (AD) continues to rise unabated, new models have been put forth to improve our understanding of this devastating condition. Although individual models may have their merits, integrated models may prove more valuable. Indeed, the reliable failures of monotherapies for AD, and the ensuing surrender of major drug companies, suggests that an integrated perspective may be necessary if we are to invent multifaceted treatments that could ultimately prove more successful. In this review article, we discuss the Wnt/Glycogen Synthase Kinase 3β (GSK3β), α-synuclein, and type 3 diabetes hypotheses of AD, and their deep interconnection, in order to foster the integrative thinking that may be required to reach a solution for the coming neurological epidemic.
In this review article, we began by summarizing the cellular, animal and human work that demonstrate dysfunctional Wnt-signaling can contribute to the development of AD and its two pathological hallmarks, Aβ plaques and p-tau tangles. We next described how the canonical PD-associated protein α-synuclein may be locked in pathological positive feedback loops with Aβ and tau. Finally, we discussed some of the mechanisms by which insulin resistance in the brain, ‘‘type 3 diabetes,’’ may contribute to development and exacerbation of AD. Throughout each section, we attempted to highlight some of the ways in which each model interacts with the others. These interrelationships, make it clear that the pathology of AD is not a linear cascade, nor a simple feedback loop, but rather a network of cross-talking models and overlapping vicious cycles.
Given the cooperative and reinforced nature of this complex network, it is no surprise that the prototypical monotherapeutic approach to AD has reliably failed. Certainly, drugs that target key nodes within the network, such as GSK3β inhibitors or AKT activators, have shown promise in animal models, and this important work affords us valuable mechanistic insights. However, these pre-clinical successes generally have not translated into clinical success, at least not with the same degree of efficacy. This is likely because animal models harboring distinct AD-causing mutations and dysfunctions in particular linear pathways do not accurately recapitulate the complex pathologies underlying sporadic human AD. In brief, we are proposing that the single-target silver-bullet approach to AD drug discovery is doomed to fail and that we may only be able to treat or prevent AD by developing new multifaceted treatment options.
Further complicating matters, the initial movers of sporadic human AD are likely highly individual. As examples, only about half of AD patients present with Lewy Body/α-synuclein pathology and there is evidence to suggest that diabetes may specifically predispose carriers of the ApoE4 risk allele to develop AD. If AD is, indeed, composed of many different subtypes, then even imagining AD as a network of reinforcing positive feedback loops, as we have done here, underestimates the pathology. We may not only need multifaceted treatment options, but personalized ones. The cost of continuing to simplify AD pathology is a continuation in the rapidly rising prevalence of AD. It is, therefore, critical that the global biomedical community take steps towards thinking more comprehensively about the mechanisms underlying AD, for only by doing so can we hope to develop multifaceted, and perhaps one day individualized, therapies to prevent or treat this devastating disease and reverse the worldwide neurodegeneration epidemic.