Marie-Kim St-Pierre

Bio: Marie-Kim St-Pierre is an academic researcher from Laval University. The author has contributed to research in topics: Microglia & Medicine. The author has an hindex of 10, co-authored 17 publications receiving 337 citations. Previous affiliations of Marie-Kim St-Pierre include University of Victoria.

Microglia Gone Rogue: Impacts on Psychiatric Disorders across the Lifespan

Abstract: Microglia are the predominant immune response cells and professional phagocytes of the central nervous system (CNS) that have been shown to be important for brain development and homeostasis. These cells present a broad spectrum of phenotypes across stages of the lifespan and especially in CNS diseases. Their prevalence in all neurological pathologies makes it pertinent to reexamine their distinct roles during steady-state and disease conditions. A major question in the field is determining whether the clustering and phenotypical transformation of microglial cells are leading causes of pathogenesis, or potentially neuroprotective responses to the onset of disease. The recent explosive growth in our understanding of the origin and homeostasis of microglia, uncovering their roles in shaping of the neural circuitry and synaptic plasticity, allows us to discuss their emerging functions in the contexts of cognitive control and psychiatric disorders. The distinct mesodermal origin and genetic signature of microglia in contrast to other neuroglial cells also make them an interesting target for the development of therapeutics. Here, we review the physiological roles of microglia, their contribution to the effects of environmental risk factors (e.g., maternal infection, early-life stress, dietary imbalance), and their impact on psychiatric disorders initiated during development (e.g., Nasu-Hakola disease (NHD), hereditary diffuse leukoencephaly with spheroids, Rett syndrome, autism spectrum disorders (ASDs), and obsessive-compulsive disorder (OCD)) or adulthood (e.g., alcohol and drug abuse, major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, eating disorders and sleep disorders). Furthermore, we discuss the changes in microglial functions in the context of cognitive aging, and review their implication in neurodegenerative diseases of the aged adult (e.g., Alzheimer's and Parkinson's). Taking into account the recent identification of microglia-specific markers, and the availability of compounds that target these cells selectively in vivo, we consider the prospect of disease intervention via the microglial route.

Impact of TREM2R47H variant on tau pathology–induced gliosis and neurodegeneration

Abstract: Alzheimer's disease (AD) is characterized by plaques containing amyloid-β (Aβ) and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau and Aβ, evidence suggests that microglia play an important role in AD pathogenesis. Rare variants in the microglia-expressed triggering receptor expressed on myeloid cells 2 (TREM2) gene increase AD risk 2- to 4-fold. It is likely that these TREM2 variants increase AD risk by decreasing the response of microglia to Aβ and its local toxicity. However, neocortical Aβ pathology occurs many years before neocortical tau pathology in AD. Thus, it will be important to understand the role of TREM2 in the context of tauopathy. We investigated the impact of the AD-associated TREM2 variant (R47H) on tau-mediated neuropathology in the PS19 mouse model of tauopathy. We assessed PS19 mice expressing human TREM2CV (common variant) or human TREM2R47H. PS19-TREM2R47H mice had significantly attenuated brain atrophy and synapse loss versus PS19-TREM2CV mice. Gene expression analyses and CD68 immunostaining revealed attenuated microglial reactivity in PS19-TREM2R47H versus PS19-TREM2CV mice. There was also a decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2R47H in the PS19 mice and in human AD brains. These findings suggest that impaired TREM2 signaling reduces microglia-mediated neurodegeneration in the setting of tauopathy.

Inflammatory mechanisms in neurodegeneration.

Abstract: This review discusses the profound connection between microglia, neuroinflammation, and Alzheimer's disease (AD). Theories have been postulated, tested, and modified over several decades. The findings have further bolstered the belief that microglia-mediated inflammation is both a product and contributor to AD pathology and progression. Distinct microglia phenotypes and their function, microglial recognition and response to protein aggregates in AD, and the overall role of microglia in AD are areas that have received considerable research attention and yielded significant results. The following article provides a historical perspective of microglia, a detailed discussion of multiple microglia phenotypes including dark microglia, and a review of a number of areas where microglia intersect with AD and other pathological neurological processes. The overall breadth of important discoveries achieved in these areas significantly strengthens the hypothesis that neuroinflammation plays a key role in AD. Future determination of the exact mechanisms by which microglia respond to, and attempt to mitigate, protein aggregation in AD may lead to new therapeutic strategies.

Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington’s disease pathology

Abstract: Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder that affects cognitive and motor abilities by primarily targeting the striatum and cerebral cortex. HD is caused by a mutation elongating the CAG repeats within the Huntingtin gene, resulting in HTT protein misfolding. Although the genetic cause of HD has been established, the specific susceptibility of neurons within various brain structures has remained elusive. Microglia, which are the brain’s resident macrophages, have emerged as important players in neurodegeneration. Nevertheless, few studies have examined their implication in HD. To provide novel insights, we investigated the maturation and dysfunction of striatal microglia using the R6/2 mouse model of HD. This transgenic model, which presents with 120+/-5 CAG repeats, displays progressive motor deficits beginning at 6 weeks of age, with full incapacitation by 13 weeks. We studied microglial morphology, phagocytic capacity, and synaptic contacts in the striatum of R6/2 versus wild-type (WT) littermates at 3, 10, and 13 weeks of age, using a combination of light and transmission electron microscopy. We also reconstructed dendrites and determined synaptic density within the striatum of R6/2 and WT littermates, at nanoscale resolution using focused ion beam scanning electron microscopy. At 3 weeks of age, prior to any known motor deficits, microglia in R6/2 animals displayed a more mature morphological phenotype than WT animals. Microglia from R6/2 mice across all ages also demonstrated increased phagocytosis, as revealed by light microscopy and transmission electron microscopy. Furthermore, microglial processes from 10-week-old R6/2 mice made fewer contacts with synaptic structures than microglial processes in 3-week-old R6/2 mice and age-matched WT littermates. Synaptic density was not affected by genotype at 3 weeks of age but increased with maturation in WT mice. The location of synapses was lastly modified in R6/2 mice compared with WT controls, from targeting dendritic spines to dendritic trunks at both 3 and 10 weeks of age. These findings suggest that microglia may play an intimate role in synaptic alteration and loss during HD pathogenesis.

mCSF-Induced Microglial Activation Prevents Myelin Loss and Promotes Its Repair in a Mouse Model of Multiple Sclerosis.

Abstract: A pathological hallmark of multiple sclerosis is myelin loss in brain white matter accompanied by compromised remyelination. Demyelinated lesions are deeply associated with oligodendrocyte apoptosis and a robust inflammatory response. Although various studies point towards a noxious role of inflammation in multiple sclerosis, others emphasize a positive role for the innate immune cells in disease progression. A cytokine well-known to stimulate cell survival, proliferation and differentiation of myeloid cells, macrophage colony-stimulating factor (mCSF), was administered to mice during a 5 week-long cuprizone diet. Treated mice exhibited reduced myelin loss during the demyelination phase, together with an increased number of microglia and oligodendrocyte precursor cells in lesion sites. Tamoxifen-induced conditional deletion of the mCSF receptor in microglia from cuprizone-fed mice caused aberrant myelin debris accumulation in the corpus callosum and reduced microglial phagocytic response. mCSF therefore plays a key role in stimulating myelin clearance by the brain innate immune cells, which is a prerequisite for proper remyelination and myelin repair processes.

Microglial subtypes: diversity within the microglial community.

Abstract: Microglia are brain‐resident macrophages forming the first active immune barrier in the central nervous system. They fulfill multiple functions across development and adulthood and under disease conditions. Current understanding revolves around microglia acquiring distinct phenotypes upon exposure to extrinsic cues in their environment. However, emerging evidence suggests that microglia display differences in their functions that are not exclusively driven by their milieu, rather by the unique properties these cells possess. This microglial intrinsic heterogeneity has been largely overlooked, favoring the prevailing view that microglia are a single‐cell type endowed with spectacular plasticity, allowing them to acquire multiple phenotypes and thereby fulfill their numerous functions in health and disease. Here, we review the evidence that microglia might form a community of cells in which each member (or “subtype”) displays intrinsic properties and performs unique functions. Distinctive features and functional implications of several microglial subtypes are considered, across contexts of health and disease. Finally, we suggest that microglial subtype categorization shall be based on function and we propose ways for studying them. Hence, we advocate that plasticity (reaction states) and diversity (subtypes) should both be considered when studying the multitasking microglia.

Interaction of Microglia and Astrocytes in the Neurovascular Unit.

Abstract: The interaction between microglia and astrocytes significantly influences neuroinflammation. Microglia/astrocytes, part of the neurovascular unit (NVU), are activated by various brain insults. The local extracellular and intracellular signals determine their characteristics and switch of phenotypes. Microglia and astrocytes are activated into two polarization states: the pro-inflammatory phenotype (M1 and A1) and the anti-inflammatory phenotype (M2 and A2). During neuroinflammation, induced by stroke or lipopolysaccharides, microglia are more sensitive to pathogens, or damage; they are thus initially activated into the M1 phenotype and produce common inflammatory signals such as IL-1 and TNF-α to trigger reactive astrocytes into the A1 phenotype. These inflammatory signals can be amplified not only by the self-feedback loop of microglial activation but also by the unique anatomy structure of astrocytes. As the pathology further progresses, resulting in local environmental changes, M1-like microglia switch to the M2 phenotype, and M2 crosstalk with A2. While astrocytes communicate simultaneously with neurons and blood vessels to maintain the function of neurons and the blood-brain barrier (BBB), their subtle changes may be identified and responded by astrocytes, and possibly transferred to microglia. Although both microglia and astrocytes have different functional characteristics, they can achieve immune "optimization" through their mutual communication and cooperation in the NVU and build a cascaded immune network of amplification.