Glial contributions to neurodegeneration in tauopathies

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.

[18F] AV-1451 uptake in corticobasal syndrome: the influence of beta-amyloid and clinical presentation

“…Given the uncertainty however over whether AV-1451 is binding 4R tau, it is also possible that the findings reflect a greater degree of neurodegeneration, i.e. neuronal cell loss, gliosis, or neuroinflammation, in premotor and precentral cortices in patients with AOS as these neurodegenerative processes are observed in corticobasal degeneration [21, 25]. It is less likely that there is more paired helical filament or mixed 3+4R Alzheimer’s type tau in these regions in CBS cases with AOS, as a pathological case study of CBS with AOS showed only 4R tau in these areas [20].…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…A novel CX3CR1 CreER R26 Confetti multiple reporter system has been used to demonstrate that microglia can regulate their cell number by clonally forming a cluster at the site of local injury (Madore, Baufeld, & Butovsky, ; Tay et al, ). As described above, reactive microglia can lead to tissue damage, exacerbate deleterious effects and potentially contribute to neurodegeneration (Leyns & Holtzman, ). As it follows that microglia play a central role in many neurological disorders (Salter & Stevens, ; Wendeln et al, ), then microglia‐directed therapy, including specific microglia depletion strategies, can be regarded as a promising immunotherapy for neurological diseases (Du et al, ; Feng et al, ; Rice et al, ).…”

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

“…Interestingly, numerous Tau kinases can be activated through inflammatory pathways such as JNK, ERK, Akt, or p38 [216]. These data suggest that neuroinflammation could contribute to, and maybe initiate, Tau pathology [217, 218]. On the other hand, inflammatory processes are also well known to affect insulin signalling.…”