Neuroimmune Tau Mechanisms: Their Role in the Progression of Neuronal Degeneration

Abstract

Progressive neurodegenerative pathologies in aged populations are an issue of major concern worldwide. The microtubule-associated protein tau is able to self-aggregate to form abnormal supramolecular structures that include small oligomers up to complex polymers. Tauopathies correspond to a group of diseases that share tau pathology as a common etiological agent. Since microglial cells play a preponderant role in innate immunity and are the main source of proinflammatory factors in the central nervous system (CNS), the alterations in the cross-talks between microglia and neuronal cells are the main focus of studies concerning the origins of tauopathies. According to evidence from a series of studies, these changes generate a feedback mechanism reactivating microglia and provoking constant cellular damage. Thus, the previously summarized mechanisms could explain the onset and progression of different tauopathies and their functional/behavioral effects, opening the window towards an understanding of the molecular basis of anomalous tau interactions. Despite clinical and pathological differences, increasing experimental evidence indicates an overlap between tauopathies and synucleinopathies, considering that neuroinflammatory events are involved and the existence of protein misfolding. Neurofibrillary tangles of pathological tau (NFT) and Lewy bodies appear to coexist in certain brain areas. Thus, the co-occurrence of synucleinopathies with tauopathies is evidenced by several investigations, in which NFT were found in the substantia nigra of patients with Parkinson's disease, suggesting that the pathologies share some common features at the level of neuroinflammatory events.

Keywords: Alzheimer’s disease; inflammation; molecular functions; molecular networks; neuroimmunomodulation; tau protein; tauopathies.

Figure 1

The potential mechanism involved in triggering tauopathies. “Damage signals” (inset at the upper left corner) sensitize resting microglia leading to an activated phenotype. This generates the over-release of increasing amounts of cytokines with the consequent effects on neuronal cells. There is activation of the protein kinase Cdk5, thus stimulating the Cdk5/p35 complex and tau hyperphosphorylation and neuronal degeneration. As a consequence of this processes, tau oligomers and PHFs are released to the extraneuronal environment, reactivating microglia via a positive feedback mechanism. This mechanism is stimulated by the ApoE4 protein. The reactivated microglia continues the cycle by increasing the levels of cytokines with the consequent effects on neuronal degeneration.