[OP.3C.01] MICROGLIAL ACTIVATION IN HYPERTENSION-MEDIATED COGNITIVE IMPAIRMENT

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Abstract

Objective:

The contribution of hypertension in the pathological cascade of vascular cognitive impairment (VCI) remains elusive, and appropriate models are lacking [1]. We have previously demonstrated an impairment of short-term memory in adult mice exposed to prolonged angiotensin II (Ang II) infusion [2]. We hypothesize that 1) the underlying mechanism involves local blood brain barrier leakages associated with microglial activations; 2) the retinal microglia reflects the state of microglial cells in the brain and could thus constitute a potential biomarker for VCI.

Design and method:

3–4 month-old male C57BL/6 mice were infused for 3 months with Ang II (2000 ng/kg/min; Ang II) or saline (Ctrl) via osmotic minipumps. Blood pressure, Garcia score, working and short-term memories (Y-maze alternation and object location tasks respectively) were assessed weekly. Plasma was collected at the end of the study to perform a cytokine array. Immunohistochemistry of brain samples was done to identify IgG leakages and microglial cells (Iba1 + ). Microglial density and soma size (indicator of activation) were measured using an automated analysis in the pre-frontal cortex (PFC), the cortex (CX), the hippocampus (HIPP), the paraventricular nucleus (PVN), and the corpus callosum (CC). Microglial density was also evaluated in flat-mounted retinas (Iba1 + ).

Results:

Amongst the identified cytokines that were upregulated in the plasma of hypertensive mice, C5a was the most upregulated. IgG leakages were 12 times larger in Ang II than Ctrl (p = 0.04). Microglial activations were often associated with IgG leakages. Microglial density was increased in the CX, HIPP and CC while microglial soma was increased in CX, HIPP (pAngII < 0.001 density, soma, see Figure). However, retinal microglial density remained unchanged.

Conclusions:

Prolonged Ang II-induced hypertension is associated with a pro-inflammatory profile, BBB leakages and local microglial activations. The retinal microglia was not affected by hypertension, suggesting it cannot be used as a biomarker of hypertension-mediated VCI. Neuronal loss and white matter integrity, as potential consequences of microglial activations, are currently being investigated to better understand the initiation of hypertension-mediated cognitive impairment.

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