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Oligodendrocyte progenitor cells (OPCs) are responsible for generating oligodendrocytes, the myelinating cells of the CNS. Life-long myelination is promoted by neuronal activity and is essential for neural network plasticity and learning. OPCs are known to contact synapses and it is proposed that neuronal synaptic activity in turn regulates their behavior. To examine this in the adult, we performed unilateral injection of the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of adult mice. We confirm BoNT/A cleaves SNAP-25 in the CA1 are of the hippocampus, which has been proven to block neurotransmission. Notably, BoNT/A significantly decreased OPC density and caused their shrinkage, as determined by immunolabeling for the OPC marker NG2. Furthermore, BoNT/A resulted in an overall decrease in the number of OPC processes, as well as a decrease in their lengths and branching frequency. These data indicate that synaptic activity is important for maintaining adult OPC numbers and cellular integrity, which is relevant to pathophysiological scenarios characterized by dysregulation of synaptic activity, such as age-related cognitive decline, Multiple Sclerosis and Alzheimer's disease.

Myelin disruption is a feature of natural aging and of Alzheimer’s disease (AD). In the CNS, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Here, we examined age-related changes in OPCs in APP/PS1 mice, a model for AD-like pathology, compared with non-transgenic (Tg) age-matched controls. Analysis was performed in the CA1 area of the hippocampus following immunolabelling for NG2 with the nuclear dye Hoescht, to identify OPC and OPC sister cells, a measure of OPC replication, together with Gpr17 and Olig2 for oligodendrocytes and myelin basic protein (MBP) immunostaining as a measure of myelination. The results indicate a decrease in the number of OPCs between 9 and 14 months in natural ageing and this occurred earlier at 9 months in APP/PS1 mice, without further decline at 14 months. The number of OPC sister cells was unaltered in natural aging, but declined significantly at 14-months in APP/PS1 mice. The number of GPR17+ and Olig2+ oligodendrocytes was not altered in APP/PS1, whereas MBP immunostaining increased between 9 and 14 months in natural ageing, but not in APP/PS1 mice. Notably, OPCs displayed marked morphological changes at 14 months in APP/PS1 mice, characterized by an overall shrinkage of OPC process domains and increased process branching, characteristic of reactive pathological changes. The results indicate that OPC and myelin disruption are pathological signs in the APP/PS1 mouse model of AD.

Microglia are the main resident immunocompetent cells of the brain with key roles in brain development, homeostasis, and function. Recent reports have started to shed light on the homeostatic mechanisms regulating the composition and turnover of the microglial population under physiological conditions from development to ageing, but our knowledge of the dynamics of microglia is incomplete. Therefore, it appears relevant to provide a standardized approach to quantify the turnover of microglia, with direct application to create a greater understanding of the dynamics of this cell population, and how it may contribute to the pathogenesis and/or progression of neurological disorders. Here we describe a robust immunohistochemical method to analyze microglial proliferation in mouse brain, aiming at providing a shared and universal approach to analyze microglial dynamics across different laboratories.

Summary The sustained proliferation of microglia is a key hallmark of Alzheimer’s disease (AD), accelerating its progression. Here, we aim to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesizing that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We show that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterized by increased βgal activity, a senescence-associated transcriptional signature, and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. The prevention of early microglial proliferation hinders the development of senescence and DAM, impairing the accumulation of Aβ, as well as associated neuritic and synaptic damage. Overall, our results indicate that excessive microglial proliferation leads to the generation of senescent DAM, which contributes to early Aβ pathology in AD., Graphical abstract, Highlights • In Alzheimer’s-like pathology, a fraction of microglia undergo replicative senescence • Disease-associated microglia (DAM) display several features of senescence • Prevention of proliferation impairs the development of microglial senescence and DAMs • Prevention of microglial senescence leads to reduced amyloidosis and synaptic damage, Hu et al. show that microglia undergo replicative senescence in a model of Alzheimer’s-like pathology. Senescence is enriched in disease-associated microglia and is caused by the accumulation of proliferative cycles. Prevention of microglial senescence leads to diminished pathology, highlighting a link of microglia with the early stages of Alzheimer’s disease.

Microglia are the main resident immunocompetent cells of the brain with key roles in brain development, homeostasis, and function. Recent reports have started to shed light on the homeostatic mechanisms regulating the composition and turnover of the microglial population under physiological conditions from development to ageing, but our knowledge of the dynamics of microglia is incomplete. Therefore, it appears relevant to provide a standardized approach to quantify the turnover of microglia, with direct application to create a greater understanding of the dynamics of this cell population, and how it may contribute to the pathogenesis and/or progression of neurological disorders. Here we describe a robust immunohistochemical method to analyze microglial proliferation in mouse brain, aiming at providing a shared and universal approach to analyze microglial dynamics across different laboratories.