Abstract 149: CD36 in Perivascular Macrophages Contributes to Neurovascular and Cognitive Dysfunction and Amyloid Angiopathy in Mice Overexpressing the Alzheimer Aβ Peptide

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Abstract

Amyloid-β (Aβ) exerts deleterious effects on the cerebral microcirculation, which may play a role in Alzheimer’s disease and mixed dementias. In mouse models of amyloid precursor protein (APP) overexpression, the vascular effects of Aβ require the innate immunity receptor CD36 in perivascular macrophages (PVM), immune cells located in the Virchow-Robin space surrounding penetrating cerebral vessels. PVM, in turn, induce vascular oxidative stress and dysfunction via NADPH oxidase (Park et al., Circ Res 2017). However, whether CD36 in PVM is involved in the cognitive impairment induced by Aβ remains unknown. We transplanted CD36-/- bone marrow (BM) into irradiated male APP-overexpressing mice (Tg2576) (age 12 months) to repopulate their perivascular space with CD36-/- PVM. Three months later, cerebral blood flow (CBF) was measured by laser-Doppler flowmetry in the somatosensory cortex of anesthetized mice with a cranial window (n=5/group). Cognition was also tested (n=10/group). In Tg2576 mice transplanted with WT BM (Wt→Tg), CBF responses induced by whisker stimulation (WS) or neocortical superfusion of the endothelium-dependent vasodilator acetylcholine (ACh) were attenuated compared to WT mice receiving WT BM (Wt→Wt) (WS, -35%; ACh, -36%; p<0.05). CD36-/- BM transplantation in Tg2576 mice (CD36-/-→Tg) prevented the cerebrovascular dysfunction (CBF increases: WS: Wt→Tg, 9±1% vs. CD36-/-→Tg, 21±2%; ACh: Wt→Tg, 9±1% vs CD36-/-→Tg, 17±2%; p<0.05), and reduced cerebrovascular amyloid deposition (thioflavin-S-based vascular amyloid load: -58%; p<0.05 from Wt→Tg). Wt→Tg mice spent more time finding the escape hole at the Barnes maze test, indicating impairment in spatial memory (Wt→Wt, 965±166 sec; Wt→Tg, 1807±166 sec; p<0.05), and showed impaired nest building ability (nesting score: Wt→Wt, 4.6±0.2; Wt→Tg, 1.8±0.2; p<0.05). These cognitive deficits were ameliorated in CD36-/-→Tg mice (Barnes maze: 1217±136 sec; nesting score: 2.7±0.3; p<0.05 from Wt→Tg). We conclude that CD36 in PVM is critically involved in the cerebrovascular and cognitive dysfunctions induced by Aβ, and in cerebral amyloid angiopathy. CD36 in PVM may be a new therapeutic target to counteract the detrimental neurovascular and cognitive effects of amyloid pathology.

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