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.

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

“…However, 28 days after tauopathy induction in vivo, a clear cognitive decline was observed. At this point, neuroinflammation was still present which is in line with previous reports that indicate that neuroinflammation occurs during tauopathy, and that it can contribute to the spreading of pathological tau in the brain and lead to dementia. Most probably, the neuroinflammatory response is a consequence of the proteinopathy induced by hyperphosphorylated tau as shown for other aggregates of proteins such as Aβ.…”

Tau protein aggregation is associated with cellular senescence in the brain

“…Pathogenic tau induces a traditional neuroinflammatory response by activating microglia and astrocytes (for recent review Laurent, Buee, & Blum, 2018). Our data suggest that NFT‐containing neurons may be active participants in perpetuating the inflammatory response as well.…”

Neuroinflammation in mouse models of Alzheimer's disease

“…b). Regulation of the glial response might therefore change markedly depending on the pathological stage of tauopathy . However, it is still unclear which glial cells, astrocytes or microglia, recognize these abnormal protein aggregates as danger signals, and how this is achieved, especially considering that the communication between astrocytes and microglia is regulated by pathology‐associated cytokines/chemokines.…”