TY - JOUR
T1 - Microglia as a critical player in both developmental and late-life CNS pathologies
AU - Derecki, Noël C.
AU - Katzmarski, Natalie
AU - Kipnis, Jonathan
AU - Meyer-Luehmann, Melanie
N1 - Funding Information:
Acknowledgments we would like to thank Joanna McCarter and Andrew Harborne for excellent comments on the manuscript. This work was supported by a grant from the Rett Syndrome Research Trust (to J. K.) and from the National Institutes of Neurological Disorders and Stroke NS081026 (to J. K), the emmy Noether Program of the German Research Foundation (DFG) (to M.M.-L) and the Hans and Ilse Breuer Foundation (M.M.-L.).
PY - 2014/9
Y1 - 2014/9
N2 - Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer's disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies. In a mouse model of Rett syndrome, bone marrow transplant and CNS engraftment of microglia-like cells were associated with surprising improvements in pathology-these benefits were abrogated by block of phagocytic function. In Alzheimer's disease, large-scale genome-wide association studies have been brought to bear as a method of identifying previously unknown susceptibility genes, which highlight microglial receptors as promising novel targets for therapeutic modulation. Multi-photon in vivo microscopy has provided a method of directly visualizing the effects of manipulation of these target genes. Here, we review the latest findings and concepts emerging from the rapidly growing body of literature exemplified for Rett syndrome and late-onset, sporadic Alzheimer's disease.
AB - Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer's disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies. In a mouse model of Rett syndrome, bone marrow transplant and CNS engraftment of microglia-like cells were associated with surprising improvements in pathology-these benefits were abrogated by block of phagocytic function. In Alzheimer's disease, large-scale genome-wide association studies have been brought to bear as a method of identifying previously unknown susceptibility genes, which highlight microglial receptors as promising novel targets for therapeutic modulation. Multi-photon in vivo microscopy has provided a method of directly visualizing the effects of manipulation of these target genes. Here, we review the latest findings and concepts emerging from the rapidly growing body of literature exemplified for Rett syndrome and late-onset, sporadic Alzheimer's disease.
KW - Alzheimer's disease
KW - Amyloid plaques
KW - Genome-wide association studies (GWAS)
KW - In vivo two-photon microscopy
KW - Mecp2
KW - Microglia
KW - Phagocytosis
KW - Rett syndrome
UR - http://www.scopus.com/inward/record.url?scp=84906307352&partnerID=8YFLogxK
U2 - 10.1007/s00401-014-1321-z
DO - 10.1007/s00401-014-1321-z
M3 - Review article
C2 - 25056803
AN - SCOPUS:84906307352
SN - 0001-6322
VL - 128
SP - 333
EP - 345
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 3
ER -