Circulating Angiotensin-(1–7) Is Reduced in Alzheimer’s Disease Patients and Correlates With White Matter Abnormalities: Results From a Pilot Study

Abstract

IntroductionAlzheimer’s disease (AD) is the leading cause of dementia worldwide. Despite the extensive research, its pathophysiology remains largely unelucidated. Currently, more attention is being given to the disease’s vascular and inflammatory aspects. In this context, the renin-angiotensin system (RAS) emerges as a credible player in AD pathogenesis. The RAS has multiple physiological functions, conducted by its two opposing axes: the classical, led by Angiotensin II (Ang II), and the alternative, driven by Angiotensin-(1–7) [Ang-(1–7)]. These peptides were shown to interact with AD pathology in animal studies, but evidence from humans is scarce. Only 20 studies dosed RAS molecules in AD patients’ bloodstream, none of which assessed both axes simultaneously. Therefore, we conducted a cross-sectional, case-control exploratory study to compare plasma levels of Ang II and Ang-(1–7) in AD patients vs. age-matched controls. Within each group, we searched for correlations between RAS biomarkers and measures from magnetic resonance imaging (MRI).MethodsWe evaluated patients with AD (n = 14) and aged-matched controls (n = 14). Plasma Ang II and Ang-(1–7) were dosed using ELISA. Brain MRI was performed in a 3 Tesla scan, and a three-dimensional T1-weighted volumetric sequence was obtained. Images were then processed by FreeSurfer to calculate: (1) white matter hypointensities (WMH) volume; (2) volumes of hippocampus, medial temporal cortex, and precuneus. Statistical analyses used non-parametrical tests (Mann-Whitney and Spearman).ResultsAng-(1–7) levels in plasma were significantly lower in the AD patients than in controls [median (25th–75th percentiles)]: AD [101.5 (62.43–126.4)] vs. controls [209.3 (72–419.1)], p = 0.014. There was no significant difference in circulating Ang II. In the AD patients, but not in controls, there was a positive and significant correlation between Ang-(1–7) values and WMH volumes (Spearman’s rho = 0.56, p = 0.038). Ang-(1–7) did not correlate with cortical volumes in AD or in controls. Ang II did not correlate with any MRI variable in none of the groups.ConclusionIf confirmed, our results strengthen the hypothesis that RAS alternative axis is downregulated in AD, and points to a possible interaction between Ang-(1–7) and cerebrovascular lesions in AD.

Renin-Angiotensin System in Huntington′s Disease: Evidence from Animal Models and Human Patients

“…In line with our findings, previous studies have demonstrated impairments in the ACE2/Ang-(1-7)/Mas receptor axis in other neurodegenerative diseases [ 18 , 21 , 39 , 46 , 47 ]. For instance, decreased levels of Ang-(1-7) were reported in the prefrontal cortex and hippocampus of senescence-accelerated mouse prone 8 (SAMP8) mice, a model for examining the pathophysiology of early changes in AD [ 48 ].…”

“…The effects of Ang-(1-7) oppose the major responses induced by Ang II [ 12 , 14 , 15 ]. Apart from peripheral systems, the RAS components have also been found in the brain [ 16 , 17 ], prompting the investigation of the potential pathophysiological roles played by RAS in neuropsychiatric disorders [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] including HD [ 26 , 27 ].…”

The Altered Anatomical Distribution of ACE2 in the Brain With Alzheimer’s Disease Pathology

“…(2) Systemic Ang (1-7) is important to cerebral blood flow regulation and blood-brain barrier integrity. Plasma Ang (1-7) seems to be reduced in AD patients (Jiang et al, 2016;Ribeiro et al, 2021). This lack of circulating Ang (1-7) could result in an impaired neurovascular coupling and a disrupted bloodbrain barrier (Kehoe, 2018;Wright and Harding, 2019;Ribeiro et al, 2020).…”

Genetic polymorphisms in the renin-angiotensin system and cognitive decline in Parkinson’s disease

“…Although a preliminary genetic analysis in neurodegenerative diseases showed no significant expression changes in human subjects [ 40 ], some alterations in Ang-(1-7) or ACE2 protein levels in AD and PD have been revealed. Ang-(1-7) plasma levels were decreased in both PD and AD patients compared to the controls [ 41 – 43 ]. Moreover, the plasma concentration of Ang-(1-7) positively correlated with cognitive functions in AD [ 42 ].…”