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.

Neuroinflammation as a Common Feature of Neurodegenerative Disorders

“…In this context, this is where our theory of neuroimmunomodulation plays an important role and focuses on the link between neuronal damage and brain inflammatory process, mediated by the progressive activation of astrocytes and microglial cells with the consequent overproduction of proinflammatory agents (Maccioni et al, 2009). Despite clinical and pathological differences, increasing experimental evidence indicates that neuroinflammatory events lead to tau protein misfolding (Cortes et al, 2018).…”

“…These neurodegenerative disorders (tauopathies) do not have a defined clinical, biochemical, and morphological characteristic, like other diseases. Neurodegenerative disorders are distinguished by accumulation of misfolded proteins, such as α-synuclein (α-syn) protein in Parkinson’s disease (PD) and tau protein in AD (Cortes et al, 2018). An important group of degenerative diseases are the so-called tauopathies, which consist in the pathological accumulation of tau protein in intracellular fibrillary aggregates.…”

Increasing Tau 4R Tau Levels Exacerbates Hippocampal Tau Hyperphosphorylation in the hTau Model of Tauopathy but Also Tau Dephosphorylation Following Acute Systemic Inflammation

“…To the best of our knowledge, no study has investigated whether specific tau isoforms differentially modulate immune responses. 3R and 4R tau were reported to differ in their physiological function and pathological role (68), and interplays between tau mechanisms and immune responses are thought to contribute to tau pathogenesis (71,72). We therefore hypothesized that increasing the abundance of 4R tau would impact on tau pathology as well as on behavioral and physiological responses to mild systemic inflammation induced by LPS.…”

“…Altered immune status is a common feature of tauopathies (71,72), regardless of their classification in terms of 3R/4R predominance. To the best of our knowledge, no study has investigated whether specific tau isoforms differentially modulate immune responses.…”

The Role of Natural Compounds and their Nanocarriers in the Treatment of CNS Inflammation

“…Both events contribute to neuronal cell death and progressive damages to the brain tissue. Several studies have reported that chronic neuroinflammation related to the over-activation of microglia and astrocytes can accelerate tau hyperphosphorylation and Aβ aggregation via the overproduction of pro-inflammatory cytokines [ 40 , 41 , 42 ]. PD is another chronic and progressive neurodegenerative disease with the continuous loss of dopaminergic neurons, thereby inducing motor, cognitive, and neuropsychiatric dysfunction.…”