Tau and neuroinflammation: What impact for Alzheimer's Disease and Tauopathies?

Abstract

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder and the most common type of dementia (60-80% of cases). In 2016, nearly 44 million people were affected by AD or related dementia. AD is characterized by progressive neuronal damages leading to subtle and latter obvious decline in cognitive functions including symptoms such as memory loss or confusion, which ultimately require full-time medical care. Its neuropathology is defined by the extracellular accumulation of amyloid-β (Aβ) peptide into amyloid plaques, and intraneuronal neurofibrillary tangles (NFT) consisting of aggregated hyper- and abnormal phosphorylation of tau protein. The latter, identified also as Tau pathology, is observed in a broad spectrum of neurological diseases commonly referred to as "Tauopathies". Besides these lesions, sustained neuroinflammatory processes occur, involving notably micro- and astro-glial activation, which contribute to disease progression. Recent findings from genome wide association studies further support an instrumental role of neuroinflammation. While the interconnections existing between this innate immune response and the amyloid pathogenesis are widely characterized and described as complex, elaborated and evolving, only few studies focused on Tau pathology. An adaptive immune response takes place conjointly during the disease course, as indicated by the presence of vascular and parenchymal T-cell in AD patients' brain. The underlying mechanisms of this infiltration and its consequences with regards to Tau pathology remain understudied so far. In the present review, we highlight the interplays existing between Tau pathology and the innate/adaptive immune responses.

Keywords: Alzheimer's disease; Astrocytes; Glia; Inflammation; Microglia; Tau.

Fig. 1

Innate Immune response and Tau pathology: a vicious circle. Hyperphosphorylated pathological Tau species can be secreted extracellularly, explaining the progressive spread of tauopathy (A). Therefore, it promotes microglial activation/reactive astrocytes which release cytokines or neurotoxic inflammatory molecules including IL1β or TNFα (B). By a modulation of Tau kinases (p38, cdk5…), glial activation enhances Tau pathology, self-perpetuating the detrimental circle (C). Also, microglia was observed to be involved in Tau propagation by releasing exosomal Tau once pathological Tau phagocytosed (D).

Fig. 2

Consequences of T cell infiltration in Tauopathies. Along the disease formation, innate immune subsets release chemokines (eg. CCL3…) favoring brain T Cell infiltration (A). Consequently, either beneficial or detrimental effects may occur depending on the infiltrated subset. It can modulate the neuroimmune response which may impact tau pathology and synaptic functions (B). Activated T cells can also dampen neurons integrity by the release of neurotoxic factors (granzyme, perforin…) using TCR/MHC I interaction (C). TCR. T-cell receptor, MHC I. Major histocompatibility complex.