Targeting Tau: The future of defeating Alzheimer’s Disease?

Nitin Agrawal

Introduction. Alzheimer’s Disease is progressive neurodegeneration that is associated with beta-amyloid protein plaques and tau tangle accumulations1. Historically, the amyloid hypothesis, which states that the buildup of beta-amyloid plaques causes direct synaptic damage leading to cell death with brain atrophy, has been touted as the main explanation for Alzheimer’s Disease pathophysiology2,3. However, recently, there is renewed interest in determining the role of tau proteins. While physiologic tau is important for axonal transport of neurons, hyperphosphorylation of tau disrupts this physiological role and evidence increasingly points to tau being key to Alzheimer’s Disease pathophysiology instead of beta-amyloid plaques4,5. This leads to the fundamental question of how abnormal tau proteins elicit the conditions associated with Alzheimer’s Disease and whether these mechanisms are viable drug targets that can help stop the progression, or even cure, the disease. This presentation attempts to elucidate what is currently known about tauopathy in relation to Alzheimer’s Disease and what is needed going forward.           Methods. Articles from a wide variety of journals were utilized in this presentation. Most experimental articles utilized mouse models. Control mice were either wildtype or those with overexpression of human tau protein while the experimental mice had not only overexpression of tau but also induction of hyperphosphorylation of tau6,7. The main studies in this presentation utilized Western blotting, immunofluorescence and X-34 staining in order to identify tau aggregates4,6,7. Statistical analysis was performed when possible to determine statistically significant differences. Results. Hyperphosphorylation of tau proteins leads to disruption of its physiological role and accumulation in different areas of the brain. Early accumulation tends to occur in the medial temporal lobe while latter accumulation seems to be in the limbic lobe6. Hyperphosphorylation leads to abnormal activation of the unfolded protein response and abnormal inactivation of the endoplasmic reticulum associated degradation process resulting in toxic proteins7. Importantly, tauopathy relies on tau spreading through both direct neuronal connections and extracellular transfer (via neuropil and brain ventricles)4,8. Conclusions. Many studies have found that hyperphosphorylated tau leads to abnormal functions that can cause Alzheimer’s Disease pathophysiology. Increasingly, more and more research supports tauopathy as the major contributor to Alzheimer’s Disease. While various drugs have been developed in order to target specific mechanisms related to tauopathy, there is no definitive treatment yet. Ultimately, preventing aggregation of tau tangles or preventing its spread through different neurons may be key to either stopping Alzheimer’s Disease progression or possibly even curing it.

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  2. Hardy, J. “The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics.”Science 297.5580 (2002): 353-56.
  3. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Molecular Medicine. 2016;8(6):595-608
  4. Wu, J. W., Hussaini, S. A., Bastille, I. M., Rodriguez, G. A., et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nature Neuroscience. 2016;19(8): 1085-1092
  5. Metcalfe, Maria Jose, and Maria E. Figueiredo-Pereira. “Relationship Between Tau Pathology and Neuroinflammation in Alzheimer’s Disease.”Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine 77.1 (2010): 50-58.
  6. Helboe, L., Egebjerg, J., Barkholt, P., & Volbracht, C. Early depletion of CA1 neurons and late neurodegeneration in a mouse tauopathy model. Brain Research. 2017;1665(17): 22-35
  7. Abisambra, J., Jinwal, U., Blair, L., et al. Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. Alzheimer’s & Dementia. 2013;9(4): 9498 – 9507
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