Bone Marrow-Derived Microglia Play a Critical Role in Restricting Senile Plaque Formation in Alzheimer's Disease

Abstract

Microglia are the immune cells of the brain. Here we show a massive infiltration of highly ramified and elongated microglia within the core of amyloid plaques in transgenic mouse models of Alzheimer's disease (AD). Many of these cells originate from the bone marrow, and the beta-amyloid-40 and -42 isoforms are able to trigger this chemoattraction. These newly recruited cells also exhibit a specific immune reaction to both exogenous and endogenous beta-amyloid in the brain. Creation of a new AD transgenic mouse that expresses the thymidine kinase protein under the control of the CD11b promoter allowed us to show that blood-derived microglia and not their resident counterparts have the ability to eliminate amyloid deposits by a cell-specific phagocytic mechanism. These bone marrow-derived microglia are thus very efficient in restricting amyloid deposits. Therapeutic strategies aiming to improve their recruitment could potentially lead to a new powerful tool for the elimination of toxic senile plaques.

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…In addition to resident microglia, mononuclear cells that are recruited from the blood are key players in AD pathogenesis; in fact, depletion of this cell pool or ablation of the receptor protein that recruits monocytes into the brain, accelerated Ab accumulation and animal mortality ( [68,212]). On the other hand, anti-inflammatory agents such as COX-1 inhibitors induced a dose-dependent reduction in pathology in humans and transgenic mouse model of AD [154].…”

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

“…Although the irradiation and transplantation procedure provides the possibility to examine the importance of a particular gene in the hematopoietic system, it has been reported to compromise the immune response in the brain of the recipients and lead to a substantial infiltration of bone-marrow derived microglia (Simard et al, 2006). Moreover, some of the observed effects of microglia entering the brain were suggested to be directly related to the irradiation effects on the blood-brain barrier (Ajami et al, 2007;Lucin and Wyss-Coray, 2009).…”

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

“…The activated UPR was enhanced in neurons with a diffuse pattern of phosphorylated tau [128], thus, suggesting that the UPR activation requires tau but precedes formation of neurofibrillary tau tangles. Microglia and infiltrating mononuclear phagocytes are recruited to amyloid  plaques, become activated and phagocytose amyloid  leading to activation of the NLRP3 inflammasome and production of pro-inflammatory cytokines, specifically IL-1 [130][131][132][133][134]. AD patients and rodent models showed increased IL-1 expression in microglia isolated from amyloid  plaques and increased CSF levels of IL-1 [135].…”