Abstract
Monocytes emigrate from bone marrow, can infiltrate into brain, differentiate into microglia and clear amyloid β (Aβ) from the brain of mouse models of Alzheimer's disease (AD). Here we show that these mechanisms specifically require CC-chemokine receptor 2 (CCR2) expression in bone marrow cells (BMCs). Disease progression was exacerbated in APP(Swe)/PS1 mice (transgenic mice expressing a chimeric amyloid precursor protein [APPSwe] and human presenilin 1 [PS1]) harboring CCR2-deficient BMCs. Indeed, transplantation of CCR2-deficient BMCs enhanced the mnesic deficit and increased the amount of soluble Aβ and expression of transforming growth factor (TGF)-β1 and TGF-β receptors. By contrast, transplantation of wild-type bone marrow stem cells restored memory capacities and diminished soluble Aβ accumulation in APP(Swe)/PS1 and APP(Swe)/PS1/CCR2⁻/⁻ mice. Finally, gene therapy using a lentivirus-expressing CCR2 transgene in BMCs prevented cognitive decline in this mouse model of AD. Injection of CCR2 lentiviruses restored CCR2 expression and functions in monocytes. The presence of these cells in the brain of non-irradiated APP(Swe)/PS1/CCR2⁻/⁻ mice supports the concept that they can be used as gene vehicles for AD. Decreased CCR2 expression in bone marrow-derived microglia may therefore play a major role in the etiology of this neurodegenerative disease.
Highlights
Alzheimer’s disease (AD) is a progressive and incurable disorder associated with a progressive decline of memory
To establish whether chemokine receptor 2 (CCR2) deficiency in resident or bone marrow–derived microglia is responsible for exacerbating the pathology in this mouse model of AD, we generated APPSwe/PS1 and APPSwe/PS1/ CCR2–/– mice harboring WT green fluorescent protein (GFP) or CCR2–/– bone marrow cells (BMCs); all mice exhibited a high level of chimerism (~93%, data not shown)
Memory impairment were aggravated in APPSwe/PS1 mice transplanted with CCR2–/– BMCs and APPSwe/PS1/CCR2–/– mice, as shown by the number of trials (19.6 ± 3.1 versus 23.9 ± 2.4 for APPSwe/PS1/CCR2–/–) (Figure 1B) and latency (14.8 ± 0.5 versus 18.5 ± 1.8 for APPSwe/PS1/CCR2–/–) (Figure 1D)
Summary
Alzheimer’s disease (AD) is a progressive and incurable disorder associated with a progressive decline of memory This senile dementia is characterized by neuronal loss, synaptic degeneration, presence of extracellular amyloid-βpeptide (Aβ) deposits and intracellular neurofibrillary tangles. Aβ peptide can oligomerize to form soluble oligomers (such as dimers, trimers or dodecamers [Aβ*56]) and aggregate to form protofibrils, fibrils and, amyloid plaques [1,2]. Beside these pathological hallmarks, Aβ plaques are surrounded by microglia and astrocytes [3]. Both resident microglia and newly differentiated cells that are derived from the bone marrow are frequently associated with Aβ de-
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