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, beta-amyloid (Aβ) deposition induces microglial activation and the subsequent production of pro-inflammatory neurotoxic factors. In maintaining brain homeostasis, microglia 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 (CCR2). Both affect microglia and peripheral macrophage immune responses and for the latter, cell ingress across the blood brain barrier. However, how CCL2-CCR2 signaling contributes to AD pathogenesis is not well understood. To this end, we 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 can serve to accelerate memory dysfunction. Taken together, these data support a role of CCL2 in innate immune functions relevant to AD pathogenesis.

Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies

“…Accumulating evidence has revealed that inflammatory responses mediated by MCP-1 were linked to Aβ pathology and microglia accumulations,26 and that peripheral MCP-1 may attract the blood-derived monocytes migrating to CNS 27. Meta-analysed results also demonstrated remarkably increased α1-ACT levels in both the peripheral and CSF of AD compared with the control, which were both in tight associations with dementia progression 28 29.…”

Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer's disease mouse model

“…A similar observation was made in APP/PS1*CB2 À/À mice that expressed reduced levels of CCL2 compared to APP/PS1 mice. CCL2 is responsible for the recruitment of macrophages and microglia during CNS inflammation (Shi and Pamer, 2011), and the brains of CCL2-deficient APP/PS1 mice possessed fewer microglia (Kiyota et al, 2013). This suggests that the reduced microgliosis observed in APP/PS1*CB2 À/À mice could be due to reductions in CCL2 expression resulting in an impaired ability to recruit peripheral macrophages into the CNS.…”

Presenilin-1 familial Alzheimer’s disease mutation alters hippocampal neurogenesis and memory function in CCL2 null mice

“…In AD, CCL2 levels are elevated in plasma, cerebrospinal fluid and the brain (Ishizuka et al, 1997; Sun et al, 2003). While Aβ stimulates microglia and astrocytes leading to CCL2 production (El Khoury et al, 2003), deficiencies of CCL2 and its ligand binding receptor, CCR2, underlie disease onset and tempo (El Khoury et al, 2007; Kiyota et al, 2013; Naert and Rivest, 2011). Such findings strongly support a role for chemokine signaling in AD pathogenesis.…”

“…Such findings strongly support a role for chemokine signaling in AD pathogenesis. Indeed, CCL2 deficiency accelerates impairments in hippocampal neurogenesis, learning and memory in AD mice overexpressing human APP and PS1 with FAD mutations (Kiyota et al, 2013). …”