Abstract:
:At early stages of Alzheimer's disease (AD), soluble amyloid beta (Aβ) accumulates in brain while microglia are in resting state. Microglia can recognize Aβ long after formation of plaques and release neurotoxic mediators. We examined impact of early minor activation of microglia by Toll-like receptors (TLRs) 2 and 4 agonists on Alzheimer's disease-related disturbed synaptic function and spatial memory in rats. Microglial BV-2 cells were treated by 0.1, 1, and 10 μg/mL of the TLRs ligands lipopolysaccharide, monophosphoryl lipid A (MPL), and Pam3Cys for 24 hours. Culture medium was then changed with media containing 1-μM Aβ. Tumour necrosis factor (TNF)-α and CCL3 levels were measured in the supernatant, 24 hours thereafter. One μg of TLRs ligands which was able to release low level of TNF-α and CCL3, was administered intracerebroventricularly (i.c.v) to adult male rats every 3 days for 24 days. At the half of the treatment period, Aβ1-42 was infused i.c.v (0.075 μg/hour) for 2 weeks. Finally, the following factors were measured: memory performance by Morris water maze, postsynaptic potentials of dentate gyrus following perforant pathway stimulation, hippocampal inflammatory cytokines interleukin 1 (IL-1)β and TNF-α, anti-inflammatory cytokines IL-10 and TGF-1β, microglia marker arginase 1, Aβ deposits, and the receptor involved in Aβ clearance, formyl peptide receptor 2 (FPR2). TLRs ligands caused dose-dependent release of TNF-α and CCL3 by BV-2 cells. Aβ-treated cells did not release TNF-α and CCL3, whereas those pretreated with MPL and Pam3Cys significantly released these cytokines in response to Aβ. Low-dose TLRs ligands improved the disturbance in spatial and working memory; restored the impaired long-term potentiation induced by Aβ; decreased TNF-α, and Aβ deposits; enhanced TGF-1β, IL-10, and arginase 1 in the hippocampus of Aβ-treated rats; and increased polarization of hippocampal microglia to the anti-inflammatory phenotype. The ligands increased formyl peptide receptor 2 in both BV-2 cells and hippocampus/cortex of Aβ-treated rats. Microglia can sense/clear soluble Aβ by early low-dose MPL and Pam3Cys and safeguard synaptic function and memory in rats.
journal_name
Neurobiol Agingjournal_title
Neurobiology of agingauthors
Pourbadie HG,Sayyah M,Khoshkholgh-Sima B,Choopani S,Nategh M,Motamedi F,Shokrgozar MAdoi
10.1016/j.neurobiolaging.2018.06.020subject
Has Abstractpub_date
2018-10-01 00:00:00pages
203-216eissn
0197-4580issn
1558-1497pii
S0197-4580(18)30225-2journal_volume
70pub_type
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