Abstract
Alzheimer's disease (AD) is characterized by a progressive memory decline and numerous pathological abnormalities, including amyloid β (Aβ) accumulation in the brain and synaptic dysfunction. Here we wanted to study whether these brain changes were associated with alteration in the population of monocyte subsets since accumulating evidence supports the concept that the innate immune system plays a role in the etiology of this disease. We then determined the immune profile together with expression of genes encoding synaptic proteins and neurotrophins in APPSwe/PS1 mice and their age-matched wild-type (WT) littermates. We found that the progressive cognitive decline and the dramatic decrease in the expression of numerous synaptic markers and neurotrophins correlated with a major defect in the subset of circulating inflammatory monocytes. Indeed the number of CX3CR1lowLy6-ChighCCR2+Gr1+ monocytes remained essentially similar between 5 weeks and 6 months of age in APPSwe/PS1 mice, while these cells significantly increased in 6-month-old WT littermates. Of great interest is that the onset of cognitive decline was closely associated with the accumulation of soluble Aβ, disruption of synaptic activity, alteration in the BDNF system, and a defective production in the subset of CX3CR1lowLy6-ChighCCR2+Gr1+ monocytes. However, these memory impairments can be prevented or restored by boosting the monocytic production, using a short treatment of macrophage colony-stimulating factor (M-CSF). In conclusion, low CCR2+ monocyte production by the hematopoietic system may be a direct biomarker of the cognitive decline in a context of AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting the elderly
We determined the correlation between spatial memory decline and the percentage area occupied by plaque in hippocampus in each 6-month-old APPSwe/PS1 mice
According to the previous observation, we found a marked decrease of Ly6-ChighCCR2+ monocytes in 6-month-old APPSwe/PS1 mice (Figures 6G–H), while Ly6-Cint and Ly6-Clow monocytes remained similar in WT and APPSwe/PS1 mice at the same age
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting the elderly. The two core pathological hallmarks are amyloid deposits and neurofibrillary tangles (Selkoe, 2002). These senile plaques appeared primarily in the cerebral cortex and hippocampus, leaving the brainstem and cerebellum essentially unaffected. Accumulating evidence supports a detrimental role of soluble Aβ in the brains of both AD patients (Lue et al, 1999; McLean et al, 1999) and mouse models of AD (Lesné et al, 2006, 2008; Cheng et al, 2007). Such intraneuronal and extracellular accumulation of soluble Aβ oligomers may cause neuronal dysfunctions much before than neurodegeneration (Haass and Selkoe, 2007)
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