Microglia-based therapeutic strategies for Alzheimer’s disease and related tauopathies

Resumen

The presence of abnormal intracellular aggregates of the microtubule-associated protein tau is observed across a broad spectrum of neurodegenerative disorders that are collectively known as tauopathies, such as Alzheimer’s disease (AD). In addition to toxic tau aggregates, activated astrocytes and microglia as well as an increase in inflammatory molecules such complement proteins and pro- inflammatory cytokines, collectively referred to as neuroinflammation, are other common pathological hallmarks of tauopathies. Tau pathology seems to drive microglia into a non-constructive and inflammatory state in which they secrete toxic factors and injure neurons directly or indirectly, exacerbate tau pathology, and eat synapses; therefore, the role of microglia in AD and tauopathy pathogenesis is being increasingly recognized. Despite being tau pathology the one that best correlates with AD’s cognitive decline, the interaction between microglia and tau pathology, and their respective contributions to neurodegeneration are still unclear. In this context, in this thesis we have firstly validated an inducible tauopathy mouse model optimized with key tau-related pathological alterations to evaluate not only the impact of microglia on tau pathogenesis but also its therapeutic potential. Among these, hippocampal bilateral injection of adeno-associated viral particles containing the human tau mutation P301L (AAV-hTau) induced a rapid widespread of tau pathology, followed by an early and strong gliosis, complement component 1q (C1q) deposition, and a progressive hippocampal neuronal loss and cognitive decline. Particularly interesting was the strong induction of cluster of differentiation 68 (CD68)+ activated microglia and complement component 3 (C3)+ reactive astrocytes, as well as a robust correlation among these two reactive states that jointly synchronize within time. Secondly, when we eliminated microglia at different time points of tau pathology, by chow treatment with the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622, marked neuroprotection in the absence of microglia demonstrated that activated microglia was a driving force for neurodegeneration, disease progression and phosphorylated tau (p-tau) pathogenesis. Given the multiple roles of microglia in tau pathology, neuroprotection might be explained by decreased levels of insoluble oligomeric p-tau, and a partial blockade of C3+ astrocytes induction, but also by a direct attenuation of microglial-mediated inflammation. These results point out that therapeutic strategies targeting microglia may be a highly effective approach to prevent disease progression in tau-related disorders. In this line, we also demonstrated that short-term microglial depletion with PLX5622 for subsequent endogenous repopulation holds great promise as it results protective against neurodegeneration and cognitive decline in the settings of tau pathology; though neuroprotection was lost when microglial repopulation period was extended in time. Finally, given the positive results obtained in vitro demonstrating that human amniotic epithelial cells (AEC) induce a robust anti- inflammatory and immunosuppressive phenotype in microglia-like cells (MLC) generated from bone marrow (BM) monocytes, and the potential clinical translation of enforced microglial repopulation with MLC, we strongly support further investigation of this strategy in the context of tau pathology. In conclusion, we propose that microglia-based approaches could be promising therapeutic strategies with clinical relevance for tau-related disorders. Therefore, to modulate the function of microglia in neurodegeneration with unprecedented precision, additional investigation in this area is urgently needed.