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Age-related changes in synaptic markers and monocyte subsets link the cognitive decline of APP(Swe)/PS1 mice.

ABSTRACT: Alzheimer's disease (AD) is characterized by a progressive memory decline and numerous pathological abnormalities, including amyloid ? (A?) 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 APP(Swe)/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 CX(3)CR1(low)Ly6-C(high)CCR2(+)Gr1(+) monocytes remained essentially similar between 5 weeks and 6 months of age in APP(Swe)/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 A?, disruption of synaptic activity, alteration in the BDNF system, and a defective production in the subset of CX(3)CR1(low)Ly6-C(high)CCR2(+)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.

SUBMITTER: Naert G

PROVIDER: S-EPMC3485573 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Age-related changes in synaptic markers and monocyte subsets link the cognitive decline of APP(Swe)/PS1 mice.

Naert Gaëlle G Rivest Serge S

Frontiers in cellular neuroscience 20121101

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 expressio ...[more]

PMID: 23125823

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Project description:BackgroundExposure to benzo(a)pyrene (BaP) was associated with cognitive impairments and some Alzheimer's disease (AD)-like pathological changes. However, it is largely unknown whether BaP exposure participates in the disease progression of AD.ObjectivesTo investigate the effect of BaP exposure on AD progression and its underlying mechanisms.MethodsBaP or vehicle was administered to 4-month-old APPswe/PS1dE9 transgenic (APP/PS1) mice and wildtype (WT) mice for 2 months. Learning and memory ability and exploratory behaviors were evaluated 1 month after the initiation/termination of BaP exposure. AD-like pathological and biochemical alterations were examined 1 month after 2-month BaP exposure. Levels of soluble beta-amyloid (Aβ) oligomers and the number of Aβ plaques in the cortex and the hippocampus were quantified. Gene expression profiling was used to evaluate alternation of genes/pathways associated with AD onset and progression. Immunohistochemistry and Western blot were used to demonstrate neuronal loss and neuroinflammation in the cortex and the hippocampus. Treatment of primary neuron-glia cultures with aged Aβ (a mixture of monomers, oligomers, and fibrils) and/or BaP was used to investigate mechanisms by which BaP enhanced Aβ-induced neurodegeneration.ResultsBaP exposure induced progressive decline in spatial learning/memory and exploratory behaviors in APP/PS1 mice and WT mice, and APP/PS1 mice showed severer behavioral deficits than WT mice. Moreover, BaP exposure promoted neuronal loss, Aβ burden and Aβ plaque formation in APP/PS1 mice, but not in WT mice. Gene expression profiling showed most robust alteration in genes and pathways related to inflammation and immunoregulatory process, Aβ secretion and degradation, and synaptic formation in WT and APP/PS1 mice after BaP exposure. Consistently, the cortex and the hippocampus of WT and APP/PS1 mice displayed activation of microglia and astroglia and upregulation of inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP), and NADPH oxidase (three widely used neuroinflammatory markers) after BaP exposure. Furthermore, BaP exposure aggravated neurodegeneration induced by aged Aβ peptide in primary neuron-glia cultures through enhancing NADPH oxidase-derived oxidative stress.ConclusionOur study showed that chronic exposure to environmental pollutant BaP induced, accelerated, and exacerbated the progression of AD, in which elevated neuroinflammation and NADPH oxidase-derived oxidative insults were key pathogenic events.

Dataset Information

Age-related changes in synaptic markers and monocyte subsets link the cognitive decline of APP(Swe)/PS1 mice.

Publications

Age-related changes in synaptic markers and monocyte subsets link the cognitive decline of APP(Swe)/PS1 mice.

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