Microglial activation arises after aggregation of phosphorylated-tau in a neuron-specific P301S tauopathy mouse model

Alzheimer's disease, progressive supranuclear palsy and frontotemporal dementia are characterized by neuronal expression of aberrant tau protein, tau hyperphosphorylation (pTAU), tau aggregation and neurofibrillary tangle formation sequentially culminating into neuronal cell death, a process termed tauopathy. Our aim was to address at which tauopathy stage neuroinflammation starts and to study the related microglial phenotype. We used Thy1-hTau.P301S (PS) mice expressing human tau with a P301S mutation specifically in neurons. Significant levels of cortical pTAU were present from 2 months onwards. Dystrophic morphological complexity of cortical microglia arose after pTAU accumulation concomitant with increased microglial lysosomal volumes and a significant loss of homeostatic marker Tmem119. Interestingly, we detected increases in neuronal pTAU and postsynaptic structures in the lysosomes of PS microglia. Moreover, the overall cortical postsynaptic density was decreased in 6-month-old PS mice. Together, our results indicate that microglia adopt a pTAU-associated phenotype, and are morphologically and functionally distinct from wild-type microglia after neuronal pTAU accumulation has initiated

Microglia and beyond: Immune networks in neurodegenerative diseases

Summary This thesis describes multiple central and peripheral immune cell changes during aging, in Alzheimer’s disease (AD), and multiple sclerosis (MS). In the first chapters of this thesis, we investigated the effect of aging on the immune system and searched for the aging factors involved. In the later chapters, we investigated the immune response to AD and MS pathology. Aging During aging, a general decline in immune function occurs, ultimately contributing to increased susceptibility to infections in the elderly. We found that microglial morphological complexity declines during aging and can be modulated by peripheral levels of glucocorticoids. We further discovered that peripheral factors can induce age-associated changes in the brain, and thus potentially counteract them. Consequently, we hypothesize that modulating peripheral immunity via plasma factors, such as hormones and cytokines, could combat brain aging and associated pathology. Alzheimer’s disease AD is a neurodegenerative disease that ultimately causes dementia. One of the pathological hallmarks is the deposition of abnormal tau protein in the brain. We found that this deposition induced reactive and dystrophic microglia with increased lysosomal volumes containing abnormal tau and postsynaptic structures. Together, this shows that tauopathy induces a loss of homeostatic microglia that is potentially linked to a loss of synapses. Peripheral immune cells are associated with neurodegenerative diseases as well, although fewer research attempts have investigated these cells in the context of AD. We analyzed the peripheral immune landscape of AD patients at the early and late stages of the disease and found that levels of circulating CD8+ T cells with an effector memory phenotype increased before the onset of dementia. These CD8+ T cells expressed markers associated with T cell senescence and terminal differentiation. We also found that carrying the apolipoprotein E (APOE)-4 allele, a genetic risk factor for AD, affected the expression of genes involved in lipid metabolism and T cell activation in circulating immune cells of AD patients. Together, our findings show that peripheral immune changes reflect the pathobiological events of AD. Multiple sclerosis MS is the most common chronic neurodegenerative and neuroinflammatory disease in young adults. Studies have shown that compartmentalized inflammation of the nearby leptomeninges in MS patients is associated with many aspects of cortical pathology. Still, the pathological mechanisms of meningeal inflammation-induced cortical pathology remain largely elusive. We identified two MS-specific cortical microglial populations that were associated with meningeal inflammation and neurodegeneration in post-mortem progressive MS tissue. We hypothesize that microglia initially protect neurons from meningeal inflammation-induced cell death but eventually lose these protective properties and contribute to neuronal loss. In addition, studies have shown that MS patients have increased levels of immune cells and inflammatory factors in their cerebrospinal fluid (CSF). Periventricular regions around the CSF are hotspots for MS lesions, and these lesions correlate to cortical thinning. We show the infiltration of T cells, antibody-secreting cells, and NK cells in the periventricular brain regions of MS donors. The periventricular NK cells displayed an activated and migratory phenotype in MS donors, similar to their circulating counterparts. Potentially, this reflects ongoing NK cell migration to the brain parenchyma via the CSF and periventricular brain regions in MS patients. Conclusion In this thesis, we uncovered several aspects of the peripheral and central immune response to pathobiological events during aging, in AD, and in MS. I hope that our findings, together with upcoming studies, will lead to the generation of novel immune therapies that slow or prevent neurodegeneration and cognitive decline

Glucocorticoid-mediated modulation of morphological changes associated with aging in microglia

Microglia dynamically adapt their morphology and function during increasing age. However, the mechanisms behind these changes are to date poorly understood. Glucocorticoids (GCs) are long known and utilized for their immunomodulatory actions and endogenous GC levels are described to alter with advancing age. We here tested the hypothesis that age-associated elevations in GC levels implicate microglia function and morphology. Our data indicate a decrease in microglial complexity and a concomitant increase in GC levels during aging. Interestingly, enhancing GC levels in young mice enhanced microglial ramifications, while the knockdown of the glucocorticoid receptor expression in old mice aggravated age-associated microglial amoebification. These data suggest that GCs increase ramification of hippocampal microglia and may modulate age-associated changes in microglial morphology

Single-cell profiling reveals periventricular CD56bright NK cell accumulation in multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease characterised by immune cell infiltration resulting in lesions that preferentially affect periventricular areas of the brain. Despite research efforts to define the role of various immune cells in MS pathogenesis, the focus has been on a few immune cell populations while full-spectrum analysis, encompassing others such as natural killer (NK) cells, has not been performed. Here, we used single-cell mass cytometry (CyTOF) to profile the immune landscape of brain periventricular areas - septum and choroid plexus - and of the circulation from donors with MS, dementia and controls without neurological disease. Using a 37-marker panel, we revealed the infiltration of T cells and antibody-secreting cells in periventricular brain regions and identified a novel NK cell signature specific to MS. CD56bright NK cells were accumulated in the septum of MS donors and displayed an activated and migratory phenotype, similar to that of CD56bright NK cells in the circulation. We validated this signature by multiplex immunohistochemistry and found that the number of NK cells with high expression of granzyme K, typical of the CD56bright subset, was increased in both periventricular lesions and the choroid plexus of donors with MS. Together, our multi-tissue single-cell data shows that CD56bright NK cells accumulate in the periventricular brain regions of MS patients, bringing NK cells back to the spotlight of MS pathology

Contribution of Gut Microbiota to Immunological Changes in Alzheimer’s Disease

Emerging evidence suggests that both central and peripheral immunological processes play an important role in the pathogenesis of Alzheimer’s disease (AD), but regulatory mechanisms remain unknown. The gut microbiota and its key metabolites are known to affect neuroinflammation by modulating the activity of peripheral and brain-resident immune cells, yet an overview on how the gut microbiota contribute to immunological alterations in AD is lacking. In this review, we discuss current literature on microbiota composition in AD patients and relevant animal models. Next, we highlight how microbiota and their metabolites may contribute to peripheral and central immunological changes in AD. Finally, we offer a future perspective on the translation of these findings into clinical practice by targeting gut microbiota to modulate inflammation in AD. Since we find that gut microbiota alterations in AD can induce peripheral and central immunological changes via the release of microbial metabolites, we propose that modulating their composition may alter ongoing inflammation and could therefore be a promising future strategy to fight progression of AD

Contribution of Gut Microbiota to Immunological Changes in Alzheimer’s Disease

Emerging evidence suggests that both central and peripheral immunological processes play an important role in the pathogenesis of Alzheimer’s disease (AD), but regulatory mechanisms remain unknown. The gut microbiota and its key metabolites are known to affect neuroinflammation by modulating the activity of peripheral and brain-resident immune cells, yet an overview on how the gut microbiota contribute to immunological alterations in AD is lacking. In this review, we discuss current literature on microbiota composition in AD patients and relevant animal models. Next, we highlight how microbiota and their metabolites may contribute to peripheral and central immunological changes in AD. Finally, we offer a future perspective on the translation of these findings into clinical practice by targeting gut microbiota to modulate inflammation in AD. Since we find that gut microbiota alterations in AD can induce peripheral and central immunological changes via the release of microbial metabolites, we propose that modulating their composition may alter ongoing inflammation and could therefore be a promising future strategy to fight progression of AD

Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

Meningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, thereby contributing significantly to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. By extensive analysis of cortical microglia in post-mortem progressive MS tissue, we identified cortical areas with two MS-specific microglial populations, termed MS1 and MS2 cortex. The microglial population in MS1 cortex was characterized by a higher density and increased expression of the activation markers HLA class II and CD68, whereas microglia in MS2 cortex showed increased morphological complexity and loss of P2Y12 and TMEM119 expression. Interestingly, both populations associated with inflammation of the overlying meninges and were time-dependently replicated in an in vivo rat model for progressive MS-like chronic meningeal inflammation. In this recently developed animal model, cortical microglia at 1-month post-induction of experimental meningeal inflammation resembled microglia in MS1 cortex, and microglia at 2 months post-induction acquired a MS2-like phenotype. Furthermore, we observed that MS1 microglia in both MS cortex and the animal model were found closely apposing neuronal cell bodies and to mediate pre-synaptic displacement and phagocytosis, which coincided with a relative sparing of neurons. In contrast, microglia in MS2 cortex were not involved in these synaptic alterations, but instead associated with substantial neuronal loss. Taken together, our results show that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Furthermore, our in vivo data suggests that microglia initially protect neurons from meningeal inflammation-induced cell death by removing pre-synapses from the neuronal soma, but eventually lose these protective properties contributing to neuronal loss

Adaptive immune changes associate with clinical progression of Alzheimer’s disease

Abstract Background Alzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. Methods We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). Results We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Conclusions Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology

Additional file 1 of Adaptive immune changes associate with clinical progression of Alzheimer’s disease

Additional file 1