The central role of tau in Alzheimer's disease: From neurofibrillary tangle maturation to the induction of cell death

The tau protein (tau) is one of the two hallmark proteins of Alzheimer's disease (AD) together with the amyloid beta protein (A beta). In contrast to A beta, abnormally phosphorylated tau (p-tau) can also be found in non-AD tauopathies. In AD, p-tau is the main component of intraneuronal neurofibrillary tangles, which result from aggregation of abnormally phosphorylated and folded tau. In this review, we discuss the role of p-tau pathology in Alzheimer's disease considering neuropathological, biochemical, cellular, animal model, and clinical findings. We discuss the relationship between p-tau and other AD-related proteins such as A beta and transactive response DNA-binding protein 43 (TDP-43). In light of the current state of knowledge, we conclude that p-tau aggregation known as primary age -related tauopathy (PART) may represent a prerequisite for the development of AD rather that a downstream effect of A beta toxicity. However, A beta as well as TDP-43 pathology appear to accelerate accumulation and propa-gation of p-tau pathology once initiated, ultimately leading to the full-blown picture of AD. In this context, tau seeds can induce granulovacuolar degeneration (GVD), AD-typical lesions in which the activated necrosome - required for the execution of necroptosis, a programmed form of cell death -can be found. Moreover, necrosome-exhibiting GVD is associated with a decreased neuronal density. Thus, we speculate that p-tau pathology is a major driver for neuron loss in AD via GVD-mediated necroptosis. Overall, p-tau seems to play a central role in AD as it appears to constitute a prerequisite for AD development which can then be accelerated by co-factors. This would fit in a probabilistic model of AD, in which the presence and severity of the respective co-factors such as A beta, TDP-43, and others contribute separately to AD pathogenesis as probabilistic factors with a certain weight.

Automated summary

p-tau pathology plays a crucial role in Alzheimer's disease, serving as a prerequisite for AD development. Other proteins such as A beta and TDP-43 may accelerate the accumulation and propagation of p-tau pathology, ultimately leading to the full-blown picture of AD.