Abstract
Tauopathies represent a group of neurodegenerative diseases including Alzheimer’s disease (AD) that are characterized by the deposition of filamentous tau aggregates in the brain. The pathogenesis of tauopathies starts from the formation of toxic ‘tau seeds’ from hyperphosphorylated tau monomers. The presence of specific phosphorylation sites and heat shock protein 90 facilitates soluble tau protein aggregation. Transcellular propagation of pathogenic tau into synaptically connected neuronal cells or adjacent glial cells via receptor-mediated endocytosis facilitate disease spread through the brain. While neuroprotective effects of glial cells—including phagocytotic microglial and astroglial phenotypes—have been observed at the early stage of neurodegeneration, dysfunctional neuronal-glial cellular communication results in a series of further pathological consequences as the disease progresses, including abnormal axonal transport, synaptic degeneration, and neuronal loss, accompanied by a pro-inflammatory microenvironment. Additionally, the discovery of microtubule-associated protein tau (MAPT) gene mutations and the strongest genetic risk factor of tauopathies—an increase in the presence of the ε2 allele of apolipoprotein E (ApoE)—provide important clues to understanding tau pathology progression. In this review, we describe the crucial signaling pathways and diverse cellular contributors to the progression of tauopathies. A systematic understanding of disease pathogenesis provides novel insights into therapeutic targets within altered signaling pathways and is of great significance for discovering effective treatments for tauopathies.
Highlights
Intraneuronal accumulation of neurofibrillary tangles (NFT) made of abnormally hyperphosphorylated tau is centrally involved in the pathogenesis of primary tauopathies, such as supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and secondary tauopathies such as Alzheimer’s disease (AD) [1]
The purpose of this review is to summarize the factors that contribute to the formation of tau aggregates, tau cell-to-cell propagation, and glial contributions in tauopathies, by using the scientific evidence published in the last decade that bring promising insights into the therapeutic development for tau protein pathology
In addition to the important role of CX3CR1-CX3CL1 signaling and the NLRP3 inflammasome in tau pathogenesis via the crosstalk between neurons and microglia, exo-. Even though these studies demonstrate the involvement of neuroinflammation and altered CX3CR1-CX3CL1 signaling in the spreading of tau pathology, further investigation is still needed to uncover the interplay between neuroinflammation induced by extracellular tau aggregates and disrupted phagocytosis caused by impaired CX3CR1-CX3CL1 signaling
Summary
Intraneuronal accumulation of neurofibrillary tangles (NFT) made of abnormally hyperphosphorylated tau is centrally involved in the pathogenesis of primary tauopathies, such as supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and secondary tauopathies such as Alzheimer’s disease (AD) [1]. The purpose of this review is to summarize the factors that contribute to the formation of tau aggregates, tau cell-to-cell propagation, and glial contributions in tauopathies, by using the scientific evidence published in the last decade that bring promising insights into the therapeutic development for tau protein pathology Keywords for this topic, such as tauopathies, Alzheimer’s disease, prion-like propagation, tau self-aggregation, endocytosis, neuron-glial communication, neuroinflammation, and apolipoprotein E were first chosen, and searches conducted in PubMed, Google Scholar, and Web of Science. The results of these searches were refined and categorized into cellular contributors at the early stage and later stage of neurodegeneration, based on the characterized Braak-like spatiotemporal staging scheme for tau pathology.
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