Abstract
Innate immune activation is a major contributor to Alzheimer's Disease (AD) pathophysiology, although the mechanisms involved are poorly understood. Chemokine C-C motif ligand (CCL) 2 is produced by neurons and glial cells and is upregulated in the AD brain. Transgene expression of CCL2 in mouse models of amyloidosis produces microglia-induced amyloid β oligomerization, a strong indication of the role of these activation pathways in the amyloidogenic processes of AD. We have previously shown that CCL2 polarizes microglia in wild type mice. However, how CCL2 signaling contributes to tau pathogenesis remains unknown. To address this question, CCL2 was delivered via recombinant adeno-associated virus serotype 9 into both cortex and hippocampus of a mouse model with tau pathology (rTg4510). We report that CCL2 overexpression aggravated tau pathology in rTg4510 as shown by the increase in Gallyas stained neurofibrillary tangles as well as phosphorylated tau-positive inclusions. In addition, biochemical analysis showed a reduction in the levels of detergent-soluble tau species followed by increase in the insoluble fraction, indicating a shift toward larger tau aggregates. Indeed, increased levels of high molecular weight species of phosphorylated tau were found in the mice injected with CCL2. We also report that worsening of tau pathology following CCL2 overexpression was accompanied by a distinct inflammatory response. We report an increase in leukocyte common antigen (CD45) and Cluster of differentiation 68 (CD68) expression in the brain of rTg4510 mice without altering the expression levels of a cell-surface protein Transmembrane Protein 119 (Tmem119) and ionized calcium-binding adaptor molecule 1 (Iba-1) in resident microglia. Furthermore, the analysis of cytokines in brain extract showed a significant increase in interleukin (IL)-6 and CCL3, while CCL5 levels were decreased in CCL2 mice. No changes were observed in IL-1α, IL-1β, TNF-α. IL-4, Vascular endothelial growth factor-VEGF, IL-13 and CCL11. Taken together our data report for the first time that overexpression of CCL2 promotes the increase of pathogenic tau species and is associated with glial neuroinflammatory changes that are deleterious. We propose that these events may contribute to the pathogenesis of Alzheimer's disease and other tauopathies.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which is characterized by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles resulting from tau protein hyperphosphorylation and aggregation
Basal levels of CC-chemokine ligand 2 (CCL2) in rAAV9-red fluorescent protein (RFP)-injected animals were in the low range (0.52 ± 0.1 ng/mg of protein); as expected, CCL2 expression was significantly higher in the hippocampus of rAAV9-CCL2-injected animals (10.1 ± 0.2 ng/mg of protein) resulting in a 20-fold increase when compared to rAAV9-RFP-injected control animals (Figure 1H)
We observed a significant increase in Gallyas staining in the anterior cortex (ACX) and entorhinal cortex (EC), while a trend toward increased tau burden was achieved in the HPC region (p = 0.08) of CCL2 mice when compared to RFP injected control mice (Figure 7L)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which is characterized by the formation of extracellular amyloid plaques (or senile plaques) and intracellular neurofibrillary tangles resulting from tau protein hyperphosphorylation and aggregation. Activation of microglia is indicated by morphological alterations, proliferation, increased expression of cell surface receptors, and secretion of cytokines and chemokines [1]. The CC-chemokine ligand 2 (CCL2), known as monocyte chemotactic protein-1 (MCP-1), is present in the brain and produced by microglia, neurons, activated astrocytes, and mononuclear phagocytes [5]. CCL2 binds to the CC-chemokine receptor 2 (CCR2) to regulate cell infiltration into peripheral tissue and brain during infectious and inflammatory events affecting disease processes [6,7,8]. In brain tissue of AD patients, CCL2 is present in neurons, astrocytes, reactive microglia, as well as senile plaques and micro vessels [9,10,11,12]. CCL2 seems to be a viable candidate to glial activation in the neuropathology of AD and other tauopathies
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