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

2022; Elsevier BV; Volume: 190; Linguagem: Inglês

10.1016/j.brainresbull.2022.10.006

1873-2747

Dietmar Rudolf Thal, Sandra O. Tomé,

Neuroscience and Neuropharmacology Research

The tau protein (τ) is one of the two hallmark proteins of Alzheimer's disease (AD) together with the amyloid β protein (Aβ).In contrast to Aβ, abnormal phosphorylated τ (p-τ) can also be found in non-AD tauopathies.In AD, p-τ is the main component of intraneuronal neurofibrillary tangles, which result from aggregation of abnormal phosphorylated and folded τ.In this review, we discuss the role of p-τ pathology in Alzheimer's disease considering neuropathological, biochemical, cellular, animal model, and clinical findings.We discuss the relationship between p-τ and other AD-related proteins such as Aβ and transactive response DNA-binding protein 43 (TDP-43).In light of the current state of knowledge, we conclude that p-τ aggregation known as primary age-related tauopathy (PART) may represent a prerequisite for the development of AD rather that a downstream effect of Aβ toxicity.However, Aβ as well as TDP-43 pathology appear to accelerate accumulation and propagation of p-τ pathology once initiated, ultimately leading to the full-blown picture in AD. τ seeds can induce granulovacuolar degeneration (GVD), AD-typical lesions in which the activated necrosomerequired for the execution of necroptosis, a programmed form of cell death -can be found.GVD is associated with a decreasing neuronal density.Thus, we speculate that p-τ pathology is a major driver for neuron loss in AD via GVD-mediated necroptosis.Accordingly, p-τ 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, related to the presence and severity of the respective co-factors such as Aβ, TDP-43, and others.