Abstract
Tauopathies are a broad set of neurodegenerative dementias characterized by aggregation of the tau protein into filamentous inclusions that can be found in neurons and glial cells. Activated microglia, astrocytes and elevated levels of proinflammatory molecules are also pathological hallmarks that are found in brain regions affected by tau pathology. There has been abundant research in recent years to understand the role of gliosis and neuroinflammation in neurodegenerative diseases, particularly in Alzheimer’s disease (AD) which is the most common form of dementia. AD is a tauopathy characterized by both extracellular amyloid-β plaques in addition to intracellular neurofibrillary tangles and neuropil threads containing aggregated tau protein. Accumulating evidence suggests that neuroinflammation offers a possible mechanistic link between these pathologies. Additionally, there appears to be a role for neuroinflammation in aggravating tau pathology and neurodegeneration in tauopathies featuring tau deposits as the predominant pathological signature. In this review, we survey the literature regarding inflammatory mechanisms that may impact neurodegeneration in AD and related tauopathies. We consider a physical role for microglia in the spread of tau pathology as well as the non-cell autonomous effects of secreted proinflammatory cytokines, specifically interleukin 1 beta, interleukin 6, tumor necrosis factor alpha and complement proteins. These molecules appear to have direct effects on tau pathophysiology and overall neuronal health. They also indirectly impact neuronal homeostasis by altering glial function. We conclude by proposing a complex role for gliosis and neuroinflammation in accelerating the progression of AD and other tauopathies.
Highlights
Abnormal accumulation of the tau protein into intracellular, fibrillar aggregates is observed across a broad spectrum of neurodegenerative disorders that are collectively referred to as tauopathies
A recent paper showed that single chain fragment variables derived from an anti-tau antibody decreased p-tau accumulation in the brain of PS19 tau transgenic mice indicating that microglial activation via the Fragment crystallizable (Fc) domain of an antibody is not required for the protective effect of such a treatment [185]
Accumulating evidence clearly illustrates a role for gliosis and neuroinflammation in tau pathogenesis and neurodegeneration
Summary
Abnormal accumulation of the tau protein into intracellular, fibrillar aggregates is observed across a broad spectrum of neurodegenerative disorders that are collectively referred to as tauopathies. In addition to toxic protein aggregates, activated astrocytes and microglia as well as elevated proinflammatory markers are other common pathological hallmarks of tauopathies [4, 5]. Tau is predominantly produced by neurons in the brain, it is expressed at low levels in oligodendrocytes and astrocytes and tau pathology is prevalent in these cells across tauopathies [74].
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