Systemic Candesartan Treatment Modulates Behavior, Synaptic Protein Levels, and Neuroinflammation in Female Mice That Express Human APOE4

Abstract

Evidence suggests that angiotensin receptor blockers (ARBs) could be beneficial for Alzheimer’s disease (AD) patients independent of any effects on hypertension. However, studies in rodent models directly testing the activity of ARB treatment on behavior and AD-relevent pathology including neuroinflammation, Aβ levels, and cerebrovascular function, have produced mixed results. APOE4 is a major genetic risk factor for AD and has been linked to many of the same functions as those purported to be modulated by ARB treatment. Therefore, evaluating the effects of ARB treatment on behavior and AD-relevant pathology in mice that express human APOE4 could provide important information on whether to further develop ARBs for AD therapy. In this study, we treated female and male mice that express the human APOE4 gene in the absence (E4FAD−) or presence (E4FAD+) of high Aβ levels with the ARB prodrug candesartan cilexetil for a duration of 4 months. Compared to vehicle, candesartan treatment resulted in greater memory-relevant behavior and higher hippocampal presynaptic protein levels in female, but not male, E4FAD− and E4FAD+ mice. The beneficial effects of candesartan in female E4FAD− and E4FAD+ mice occurred in tandem with lower GFAP and Iba1 levels in the hippocampus, whereas there were no effects on markers of cerebrovascular function and Aβ levels. Collectively, these data imply that the effects of ARBs on AD-relevant pathology may be modulated in part by the interaction between APOE genotype and biological sex. Thus, the further development of ARBs could provide therapeutic options for targeting neuroinflammation in female APOE4 carriers.

Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine

“…A separate study reported that inhibition of mGluR5 exerted beneficial effects exclusively in male APP/PS1 mice by decreasing amyloidosis and improving cognition, while no changes were observed in females ( Abd-Elrahman et al, 2020 ). In contrast, the angiotensin receptor blocker, candesartan cilexetil, improved performance in the novel object recognition test and reduced glial activation in female 5xFAD mice crossed with mice that were homozygous for the human APOE4 gene but had no significant effect in males ( Scheinman et al, 2021 ).…”

ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies

“…Overall, APOE4 is associated with reduced blood flow, increased arteriole stiffness, and enhanced sensitivity to hypertension [ 150 ]. As such, long-term treatment with angiotensin receptor blockers has been shown to improve memory and neuroinflammation independently of Aβ pathology in female mice expressing human APOE4 [ 151 ]. Similarly, research suggests that vascular endothelial growth factor A (VEGFA) is protective against AD in apoE4-TR mice and could be a promising therapeutic target [ 152 ].…”

Angiotensin-(1–7) as a Potential Therapeutic Strategy for Delayed Cerebral Ischemia in Subarachnoid Hemorrhage

“…Estradiol regulates the expression of AT 1 R and ACE activity in several peripheral tissues (105) and mediates dopaminergic cell damage in Parkinson's disease (106). In experimental models of Alzheimer's disease inhibition of the ACE/Ang-II/AT 1 R axis by ARBs (98) or ACEi (82, 84) had higher anti-inflammatory effects in the brain of female mice. In line with these observations, the stimulation of estrogen receptor b counteracts the negative effect of Ang-II on microglial polarization (77), highlighting a potential link between low estrogen levels and Ang-II mediated neuroinflammation in microglia.…”

“…Recent data indicate that vaccination against Ang-II inhibited astrocytic and microglial activation by stimulating basic fibroblast growth factor 2 (FGF2) signaling, and improved cognitive outcome in rats with vascular dementia ( 59 ). Neuromodulatory effects mediated by microglia and astrocytes have been reported with ARBs ( 82 , 85 , 86 , 95 , 98 – 100 ) and ACE inhibitors (ACEi) ( 82 ). Also, AT 1 R knock down by viral vector, reduced inflammatory mediators and glial activation in hypertensive rats ( 101 ).…”