Abstract
Microglia play a critical role in both homeostasis and disease, displaying a wide variety in terms of density, functional markers and transcriptomic profiles along the different brain regions as well as under injury or pathological conditions, such as Alzheimer’s disease (AD). The generation of reliable models to study into a dysfunctional microglia context could provide new knowledge towards the contribution of these cells in AD. In this work, we included an overview of different microglial depletion approaches. We also reported unpublished data from our genetic microglial depletion model, Cx3cr1CreER/Csf1rflx/flx, in which we temporally controlled microglia depletion by either intraperitoneal (acute model) or oral (chronic model) tamoxifen administration. Our results reported a clear microglial repopulation, then pointing out that our model would mimic a context of microglial replacement instead of microglial dysfunction. Next, we evaluated the origin and pattern of microglial repopulation. Additionally, we also reviewed previous works assessing the effects of microglial depletion in the progression of Aβ and Tau pathologies, where controversial data are found, probably due to the heterogeneous and time-varying microglial phenotypes observed in AD. Despite that, microglial depletion represents a promising tool to assess microglial role in AD and design therapeutic strategies.
Highlights
The contribution of microglial cells to the progression and spread of pathogenic Tau species is still a matter of debate, it has recently been described that TREM2 loss of functions increases neuritic pathology and Tau spreading in amyloidogenic models [21]
In order to further characterize microglial role in Alzheimer’s disease (AD), microglial depletion models are being combined with AD mouse models bearing either Aβ and/or Tau pathologies (Table 1)
If the microglial depletion–repopulation phenomenon was able to slow down the progression of Aβ and Tau pathologies, therapies based on microglial turnover should be designed
Summary
The primary immune cells of the brain, survey the environment for pathogens and debris, and play other important roles in the central nervous system (CNS), providing direct sustain to neurons and supporting myelinogenesis, synaptic plasticity, and the neoformation of vessels [1,2]. The contribution of microglial cells to the progression and spread of pathogenic Tau species is still a matter of debate, it has recently been described that TREM2 loss of functions increases neuritic pathology and Tau spreading in amyloidogenic models [21]. Microglial activation has been reported in several brain regions of AD patients [22,23,24], it is important to point out that, in the hippocampus, the microglial response is not as strong as reported for amyloidogenic mice and several Tau models [20,25]. Several evidences point to the decline of microglial defensive functions in AD In this sense, we have described a microglial degenerative process in the hippocampus of AD patients, mainly mediated by pathological Tau species [25,28]. Selective ablation of harmful microglia within suitable time windows and their replacement by protective microglia may be a promising therapeutic strategy for AD and other neurodegenerative diseases
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