Alzheimer’s disease (AD) constitutes a major cause of dementia, affecting more women than men. It is characterized by amyloid-β (Aβ) deposition and neurofibrillary tangles (NFTs) formation, associated with a progressive cognitive decline. Evidence indicates that AD onset increases the prevalence of cerebral microinfarcts caused by vascular pathologies, which occur in approximately in half of AD patients. In this project, we postulated that multifocal cerebral microinfarcts decisively influence early AD-like pathology progression in a sex dependent manner in young APP/PS1 mice. For this purpose, we used a novel approach to model multifocal microinfarcts in APP/PS1 mice via the sporadic occlusions of the microvasculature. Our findings indicate that microinfarcts reduced Aβ deposits without affecting soluble Aβ levels in the brain of male and female APP/PS1 mice, while causing rapid and prolonged cognitive deficits in males, and a mild and transient cognitive decline in females. In male APP/PS1 mice, microinfarcts triggered an acute hypoperfusion followed by a chronic hyperperfusion. Whereas in female APP/PS1 mice, microinfarcts caused an acute hypoperfusion, which was recovered in the chronic phase. Microinfarcts triggered a robust microglial activation and recruitment of peripheral monocytes to the lesion sites and Aβ plaques more potently in female APP/PS1 mice, possibly accounting for the reduced Aβ deposition. Finally, expression of Dickkopf-1 (DKK1), which plays a key role in mediating synaptic and neuronal dysfunction in AD, was strongly induced at the lesion sites of male APP/PS1 mice, while its expression was reduced in females. Our findings suggest that multifocal microinfarcts accelerate AD pathology more potently in young males compared to young females independently upon Aβ pathology via modulation of neurovascular coupling, inflammatory response, and DKK1 expression. Our results suggest that the effects of microinfarcts should be taken into consideration in AD diagnosis, prognosis, and therapies.

Microglia are the innate immune cells of the CNS and their proliferation, activation, and survival have previously been shown to be highly dependent on macrophage colony-stimulating factor receptor (CSF1R). Here we investigated the impact of the receptor in such processes using two different models of nerve injuries, namely hypoglossal axotomy and cuprizone-induced demyelination. Both models are associated with a robust microgliosis. The role of CSF1R was investigated using the gene deletion Cre/Lox system, which allows the conditional knockout following tamoxifen administration. We found that after 5 weeks of cuprizone diet that CSF1R suppression caused a significant impairment of microglia function. A reduced microgliosis was detected in the corpus collosum of CSF1R knockout mice compared to controls. In contrast to cuprizone model, the overall number of Iba1 cells was unchanged at all the times evaluated following hypoglossal axotomy in WT and cKO conditions. After nerve lesion, a tremendous proliferation was noticed in the ipsilateral hypoglossal nucleus to a similar level in both knockout and wild-type groups. We also observed infiltration of bone-marrow derived cells specifically in CSF1R-deficient mice, these cells tend to compensate the CSF1R signaling pathway suppression in resident microglia. Taking together our results suggest a different role of CSF1R in microglia depending on the model. In the pathologic context of cuprizone-induced demyelination CSF1R signaling pathway is essential to trigger proliferation and survival of microglia, while this is not the case in a model of systemic nerve injury. M-CSF/CSF1R is consequently not the unique system involved in microgliosis following nerve damages.

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Microglia are the innate immune cells of CNS; their proliferation, activation, and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R. Methods Here, we investigate the impact of such receptor on AD etiology and microglia. We deleted CSF1R using Cre/Lox system; the knockout (KO) is restricted to microglia in the APP/PS1 mouse model. We induced the knockout at 3 months old, before plaque formation, and evaluated both 6- and 8-month-old groups of mice. Results Our findings demonstrated that CSF1R KO did not impair microglial survival and proliferation at 6 and 8 months of age in APP cKO compared to their littermate-control groups APPSwe/PS1. We have also shown that cognitive decline is delayed in CSF1R-deleted mice. Ameliorations of AD etiology are associated with a decrease in plaque volume in the cortex and hippocampus area. A compensating system seems to take place following the knockout, since TREM2/β-Catenin and IL-34 expression are significantly increased. Such a compensatory mechanism may promote microglial survival and phagocytosis of Aβ in the brain. Conclusions Our results provide new insights on the role of CSF1R in microglia and how it interacts with the TREM2/β-Catenin and IL-34 system to clear Aβ and ameliorates the physiopathology of AD.

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Macrophage colony-stimulating factor (mCSF) is a cytokine known to promote the recruitment of macrophages inducing the release of CCL2, a chemokine mobilizing monocytes to sites of inflammation. Additionally, it induces microglia/macrophage proliferation and the polarization of these cells towards a M2-like phenotype, impairing their ability to release pro-inflammatory factors and toxic mediators, while favoring the release of mediators promoting tissue repair. Another important player is the mCSF receptor CSFR1, which is highly expressed in monocytes, macrophages and microglia. Here, we discuss the new interesting therapeutic avenue of the mCSF/CSFR1 axis on brain diseases. More specifically, mCSF cascade might stimulate the survival/proliferation of oligodendrocytes, enhance the immune response as well as modulate the release of growth factors and the phagocytic activity of immune cells to remove myelin debris and toxic proteins from the brain.