title: CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease.
abstract: Circulating monocytoid cells have the ability to infiltrate nervous tissue, differentiate into microglia, and clear amyloid-β (Aβ) from the brain of mouse models of Alzheimer's disease. Interaction between the chemokine CCL2 and its CC chemokine receptor 2 (CCR2) plays a critical role in the recruitment of inflammatory monocytes into the injured/diseased brain. Here, we show that CCR2 deficiency aggravates mnesic deficits and amyloid pathology in transgenic mice expressing the chimeric mouse/human β-amyloid precursor protein and presenilin 1 (APP(Swe)/PS1). Indeed, memory impairment was accelerated and enhanced in APP(Swe)/PS1/CCR2(-/-) mice. Apparition of cognitive decline occurred earlier (i.e., at 3 months of age before plaque formation) and correlated with intracellular accumulation of soluble oligomeric forms of Aβ. Memory deficits worsened with age and were aggravated in APP(Swe)/PS1/CCR2(-/-) mice compared with their respective control groups. Soluble Aβ assemblies increased significantly in APP(Swe)/PS1 mice in a context of CCR2 deficiency, whereas the plaque load remained relatively similar in the brain of aging APP(Swe)/PS1 and APP(Swe)/PS1/CCR2(-/-) mice. However, CCR2 deficiency stimulated the expression of TGF-β1, TGF-β receptors, and CX(3)CR1 transcripts in plaque-associated microglia, a pattern that is characteristic of an antiinflammatory subset of myeloid cells. A decreased expression of CCR2 could play a potential role in the etiology of Alzheimer's disease, a neurodegenerative pathology that could be treated by a genetic upregulation of the transgene in monocytoid cells.
authors.affiliation: Laboratory of Endocrinology and Genomics, Centre de Recherche du Centre Hospitalier de l'Université Laval Research Center and Department of Molecular Medicine, Laval University, Quebec City, Quebec G1V 4G2, Canada.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Naert
authors.forename: Serge
authors.initials: S
authors.lastname: Rivest
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016014:Linear Models; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics* / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; C515335:Ccr2 protein, mouse; D053764:Presenilin-1; D054390:Receptors, CCR2; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1