Angiotensin receptor blocker use is associated with upregulation of the memory-protective angiotensin type 4 receptor (AT4R) in the postmortem brains of individuals without cognitive impairment

Abstract

The reported primary dementia-protective benefits of angiotensin II type 1 receptor (AT₁R) blockers (ARB) are believed, at least in part, to arise from systemic effects on blood pressure. However, there is a specific and independently regulated brain renin-angiotensin system (RAS). Brain RAS acts mainly through three receptor subtypes; AT₁R, AT₂R, and AT₄R. The AT₁R promotes inflammation and mitochondrial reactive oxygen species generation. AT₂R increases nitric oxide. AT₄R is essential for dopamine and acetylcholine release. It is unknown whether ARB use is associated with changes in the brain RAS. Here, we compared the impact of treatment with ARB on not cognitively impaired individuals and individuals with Alzheimer's dementia using postmortem frontal-cortex samples of age- and sex-matched participants (70-90 years old, n = 30 in each group). We show that ARB use is associated with higher brain AT₄R, lower oxidative stress, and amyloid-β burden in NCI participants. In AD, ARB use was associated with lower brain AT₁R but had no impact on inflammation, oxidative stress, or amyloid-β burden. Our results may suggest a potential role for AT₄R in the salutary effects for ARB on the brains of not cognitively impaired older adults.

Keywords: AT4R; Alzheimer’s disease; Angiotensin receptor blocker; Brain; Inflammation; Oxidative stress.

Fig. 1

Protein levels of angiotensin receptors in not cognitively impaired groups. (A) Protein levels of angiotensin II type 1 receptor (AT₁R). (B) Angiotensin II type 2 receptor (AT₂R). (C) Angiotensin type 4 receptor (AT₄R) in not cognitively impaired (NCI) group treated (n = 30) and untreated (n = 30) with angiotensin receptor blockers (ARB). Data are presented with median and interquartile range. Comparisons were conducted using Mann–Whitney U test. (*p ≤ 0.05). au, arbitrary unit. (D) Western blot images of the AT₁R, AT₂R, and AT₄R

Fig. 2

Protein levels of angiotensin receptors in Alzheimer’s dementia groups. (A) Protein levels of angiotensin II type 1 receptor (AT₁R). (B) Angiotensin II type 2 receptor (AT₂R). (C) Angiotensin type 4 receptor (AT₄R) in Alzheimer’s dementia (AD) group treated (n = 30) and untreated (n = 30) with angiotensin receptor blockers (ARB). Data are presented with median and interquartile range. Comparisons were conducted using Mann–Whitney U test (*p ≤ 0.05). au, arbitrary unit. (D) Western blot images of the AT₁R, AT₂R, and AT₄R

Fig. 3

Brain protein carbonyl (oxidative stress marker) differences between angiotensin receptor blockers treated and untreated groups. Levels of brain protein carbonyls (PC) in (A) not cognitively impaired (NCI) group treated (n = 30) and untreated (n = 30) with angiotensin receptor blockers (ARB) and (B) Alzheimer’s dementia (AD) group treated (n = 30) and untreated (n = 30) with ARB. Data are presented with median and interquartile range. Comparisons were conducted using Mann–Whitney U test (ns, non-significant; *p ≤ 0.05)

Fig. 4

Illustration of correlation between AT₄R and cytokine levels. Scatter plot showing the correlation (and 95% confidence interval of the regression line) between levels of (A) AT₄R and brain IL-6 (n = 30) (p = 0.871) in Alzheimer’s dementia group. (B) AT₄R and brain IL-6 (n = 30) (r =  − 0.523 p = 0.003) in Alzheimer’s dementia group treated with angiotensin receptor blockers. (C) AT₄R and serum IL-1β (n = 26) (p = 0.898) in Alzheimer’s dementia group. (D) AT₄R and serum IL-1β (n = 26) (r =  − 0.460 p = 0.020) in Alzheimer’s dementia group treated with angiotensin receptor blockers. Spearman’s correlation analysis was used

Fig. 5

Amyloid-β scores in not cognitively impaired groups and Alzheimer’s dementia groups. (A) Calcarine cortex amyloid-β scores in not cognitively impaired (NCI) group treated (n = 30) and untreated (n = 26) with angiotensin receptor blockers (ARB). (B) Inferior temporal cortex amyloid-β scores in not cognitively impaired (NCI) group treated (n = 30) and untreated (n = 24) with angiotensin receptor blockers (ARB). (C) Calcarine cortex amyloid-β scores in Alzheimer’s dementia (AD) group treated (n = 30) and untreated (n = 30) with ARB. (D) Inferior temporal cortex amyloid-β scores in Alzheimer’s dementia (AD) group treated (n = 30) and untreated (n = 30) with ARB. Data are presented with median and interquartile range. Comparisons were conducted using Mann–Whitney U test (ns, non-significant; *p ≤ 0.05)

Fig. 6

Semantic memory scores and slope of the semantic memory in Alzheimer’s dementia group treated with angiotensin receptor blockers. (A) Semantic memory score in Alzheimer’s dementia (AD) group treated (n = 25) and untreated (n = 26) with ARB. (B) Slope of the semantic memory in Alzheimer’s dementia (AD) group treated (n = 30) and untreated (n = 29) with ARB. Data are presented with mean and standard deviation. Comparisons were conducted using Student’s t test (*p < 0.05)

Fig. 7

Summary of the changes with angiotensin receptor blocker (ARB) treatment in both not cognitively impaired and Alzheimer’s dementia participants. ACE, angiotensin-converting enzyme; Ang, angiotensin; ARB, angiotensin receptor blocker; AP-A, aminopeptidase A; AP-N, aminopeptidase N; AT₁R, angiotensin II type 1 receptor; AT₂R, angiotensin II type 2 receptor; AT₄R, angiotensin type 4 receptor