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CC Chemokine Receptor 2 Deficiency Aggravates Cognitive Impairments and Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease

G. Naert,S. Rivest

Published 2011 in Journal of Neuroscience

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 (APPSwe/PS1). Indeed, memory impairment was accelerated and enhanced in APPSwe/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 APPSwe/PS1/CCR2−/− mice compared with their respective control groups. Soluble Aβ assemblies increased significantly in APPSwe/PS1 mice in a context of CCR2 deficiency, whereas the plaque load remained relatively similar in the brain of aging APPSwe/PS1 and APPSwe/PS1/CCR2−/− mice. However, CCR2 deficiency stimulated the expression of TGF-β1, TGF-β receptors, and CX3CR1 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.

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