Microglia and astrocytes play essential roles in the central nervous system contributing to many functions including homeostasis, immune response, blood–brain barrier maintenance and synaptic support. Evidence has emerged from experimental models of glial communication that microglia and astrocytes influence and coordinate each other and their effects on the brain environment. However, due to the difference in glial cells between humans and rodents, it is essential to confirm the relevance of these findings in human brains. Here, we aim to review the current knowledge on microglia-astrocyte crosstalk in humans, exploring novel methodological techniques used in health and disease conditions. This will include an in-depth look at cell culture and iPSCs, post-mortem studies, imaging and fluid biomarkers, genetics and transcriptomic data. In this review, we will discuss the advantages and limitations of these methods, highlighting the understanding these methods have brought the field on these cells communicative abilities, and the knowledge gaps that remain.
Neuroinflammation is involved in the aetiology of many neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease and motor neuron disease. Whether neuroinflammation also plays an important role in the pathophysiology of frontotemporal dementia is less well known. Frontotemporal dementia is a heterogeneous classification that covers many subtypes, with the main pathology known as frontotemporal lobar degeneration. The disease can be categorized with respect to the identity of the protein that causes the frontotemporal lobar degeneration in the brain. The most common subgroup describes diseases caused by frontotemporal lobar degeneration associated with tau aggregation, also known as primary tauopathies. Evidence suggests that neuroinflammation may play a role in primary tauopathies with genome-wide association studies finding enrichment of genetic variants associated with specific inflammation-related gene loci. These loci are related to both the innate immune system, including brain resident microglia, and the adaptive immune system through possible peripheral T-cell involvement. This review discusses the genetic evidence and relates it to findings in animal models expressing pathogenic tau as well as to post-mortem and PET studies in human disease. Across experimental paradigms, there seems to be a consensus regarding the involvement of innate immunity in primary tauopathies, with increased microglia and astrocyte density and/or activation, as well as increases in pro-inflammatory markers. Whilst it is less clear as to whether inflammation precedes tau aggregation or vice versa; there is strong evidence to support a microglial contribution to the propagation of hyperphosphorylated in tau frontotemporal lobar degeneration associated with tau aggregation. Experimental evidence—albeit limited—also corroborates genetic data pointing to the involvement of cellular adaptive immunity in primary tauopathies. However, it is still unclear whether brain recruitment of peripheral immune cells is an aberrant result of pathological changes or a physiological aspect of the neuroinflammatory response to the tau pathology.
Background: Tauopathies are a group of neurodegenerative diseases associated with the accumulation of misfolded tau protein. The mechanisms underpinning tau-dependent proteinopathy remain to be elucidated. A protein quality control pathway within the endoplasmic reticulum, the unfolded protein response (UPR), has been suggested as a possible pathway modulating cellular responses in a range of neurodegenerative diseases, including those associated with misfolded cytosolic tau. Objective: In this study we investigated three different clinically defined tauopathies to establish whether these diseases are accompanied by the activation of UPR. Methods: We used PCR and western blotting to probe for the modulation of several reliable UPR markers in mRNA and proteins extracted from three distinct tauopathies: 20 brain samples from Alzheimer’s disease patients, 11 from Pick’s disease, and 10 from progressive supranuclear palsy. In each disease samples from these patients were compared with equal numbers of age-matched non-demented controls. Results: Our investigation showed that different markers of UPR are not changed at the late stage of any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls. Conclusion: These data from late-stage human cortical tissue report an activation of UPR markers within the aged brain across all cohorts investigated and further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a diseased-associated activation of UPR.
Background Frontotemporal lobar degeneration (FTLD) describes a neurodegenerative disorder caused by protein accumulation in the brain, with the most common form due to aggregated Tau (FTLD‐tau). A potential role for neuroinflammation in FTLD has been highlighted by the discovery of genetic risk variants related to innate/adaptive immunity. Furthermore, studies have shown increased microglial and astrocyte activation together with T cell infiltration in the brain of a mouse tauopathy model (THY‐Tau22). Methods To test the possible neuro‐immune interactions in human FTLD‐tau, we obtained FFPE brain tissue from 12 FTLD‐MAPT, 33 Pick’s Disease (PiD) and 45 Progressive Supranuclear Palsy (PSP) patients, as well as 55 controls. Using immunohistochemistry we assessed the tau pathology across diseases using antibodies against several sites of tau phosphorylation in association with phenotypic markers of microglia and T cells. Results Our results show that PiD, PSP and FTLD‐MAPT patients had significantly higher phosphorylated tau protein loads (AT8: p<0.001 for all, AT100: p<0.001 PiD & FTLD‐MAPT, p = 0.009 PSP) compared to controls. We also observed a significant correlation between AT8 and AT100 in all but control groups. Whilst no significant changes were seen between groups in microglial markers (Iba1, CD68 and HLA‐DR), significant associations were seen between AT8 and CD68 in control (r=0.389, p<0.004) and PSP cases (r=0.422, p<0.004), with associations between AT100 and CD68 in PiD (r=0.547, p=0.001) and FTLD‐MAPT (r=0.762, p=0.005). Conclusion These findings support the involvement of microglia in FTLD, but additional immunophenotyping is necessary for further defining their role in the disease pathogenesis.
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