Abstract
The mechanism of cognitive dysfunction caused by ischemic white matter lesions is unclear. To explore the effect and mechanism of different cell-derived adenosine A2A receptor (A2AR) in cognitive impairment caused by chronic hypoperfusion white matter lesions (CHWMLs), we destroyed the bone marrow hematopoietic capacity of the recipient mice using radiation irradiation followed by establishing the selectively inactivated or reconstituted A2AR models with the transplanting bone marrow from global A2AR gene knockout or wild-type mice into wild-type or gene knockout mice, respectively. Then Morris Water Maze (MWM), ELISA, immunohistochemistry, and Bielschowsky silver staining were used to assess the effect and mechanism of the cognitive function in chronic cerebral blood flow hypoperfusion (CCH) model. Selectively reconstructing bone marrow-derived cells (BMDCs) A2AR (WT → KO group) and activated total adenosine A2AR with CGS21680 (CCH + CGS group) improved the cognitive related index. Activation of BMDC A2AR suppressed expression of inflammatory cytokines in peripheral blood and reduced the number of activated microglia cells co-localized with cystatin F in local brain, consequently inhibited white matter lesions. On the contrary, selective inactivation of adenosine A2AR (KO → WT group) and activation of non-BMDC A2AR with CGS21680 (KO → WT + CGS group) served the opposite effects. These results suggested that BMDC A2AR could inhibit white matter lesions and attenuate cognitive impairment after CHWMLs, whereas non-BMDC A2ARs aggravate cognitive impairment. The systemic inflammatory response and local activated microglia with cystatin F high expression were involved in the process of cognitive function recovery with BMDC A2AR. The overall trend is that BMDC A2ARs play a leading role.
Highlights
Ischemic leukoencephalopathy refers to a wide range of lesions within the deep perforating arteriole in the hemispheres
After bone marrow cell transplantation, the time to find the platform hidden underwater in the groups of WT → WT, KO → WT, WT → KO, and KO → KO was gradually shortened, and there was no significant difference in escape latency (Fig. S1E), indicating that the bone marrow transplantation had no effect on the learning ability of normal mice
To further investigate the role of different cell-derived adenosine A2A receptor (A2AR) in cognitive impairment following chronic hypoperfusion white matter lesions (CHWMLs), we evaluated the effect of bone marrow-derived cells (BMDCs) A2ARs and non-BMDC A2ARs on cognitive recovery by irradiation and bone marrow transplantation
Summary
Ischemic leukoencephalopathy refers to a wide range of lesions within the deep perforating arteriole in the hemispheres. It has been reported that promoting adenosine A2AR accumulation in the hippocampus can promote cognitive improvement in schizophrenia [13], that adenosine A2AR knockdown aggravates the motor and cognitive dysfunction of Huntington’s disease by reducing the expression of morphine peptides in the striatum region, and that increasing A2A receptor expression in peripheral blood mononuclear cells can improve the prognosis of mild cognitive function disorder patients by reducing inflammation [14]. These data suggest that adenosine A2AR plays two distinct roles in the recovery of cognitive function in different diseases. The role and mechanism of adenosine A2AR in cognitive dysfunction induced by CHWMLs has not been reported, and it is worthy of further exploration
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