title: CCL2 affects β-amyloidosis and progressive neurocognitive dysfunction in a mouse model of Alzheimer's disease.
abstract: Neuroinflammation affects the pathobiology of Alzheimer's disease (AD). Notably, β-amyloid (Aβ) deposition induces microglial activation and the subsequent production of proinflammatory neurotoxic factors. In maintaining brain homeostasis, microglial plasticity also enables phenotypic transition between toxic and trophic activation states. One important control for such cell activation is through the CC-chemokine ligand 2 (CCL2) and its receptor, the CC-chemokine receptor 2. Both affect microglia and peripheral macrophage immune responses and for the latter, cell ingress across the blood-brain barrier. However, how CCL2-CC-chemokine receptor 2 signaling contributes to AD pathogenesis is not well understood. To this end, we now report that CCL2 deficiency influences behavioral abnormalities and disease progression in Aβ precursor protein/presenilin-1 double-transgenic mice. Here, increased cortical and hippocampal Aβ deposition is coincident with the formulation of Aβ oligomers. Deficits in peripheral Aβ clearance and in scavenger, neuroprogenitor, and microglial cell functions are linked to deficient Aβ uptake. All serve to accelerate memory dysfunction. Taken together, these data support a role of CCL2 in innate immune functions relevant to AD pathogenesis.
authors.affiliation: Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 5930, USA. tkiyota@unmc.edu
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kiyota
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weir
authors.forename: E Elizabeth
authors.initials: EE
authors.lastname: Higgins
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.forename: Mohit
authors.initials: M
authors.lastname: Jain
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000150:complications / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism*; D003072:Cognition Disorders / Q000150:complications / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D016229:Amyloid beta-Peptides; C111835:CCL2 protein, human; D018932:Chemokine CCL2