Averting dementia: renin-angiotensin system and angiogenic cells in cognitive decline

2019-01-03Introduction: Alzheimer's disease (AD) is an insidious neurodegenerative disease that initially manifests as memory loss. Cognitive function progressively worsens over time, and ultimately results in death. Modifiable risk factors such as midlife hypertension can increase the risk of developing AD later in life. Clinical studies have found that angiotensin II receptor blockers (ARBs) may confer additional protection against cognitive decline beyond its antihypertensive actions. The mechanisms underlying this additional protection may lie beyond controlling blood pressure, but rather through the metabolism of angiotensin II to angiotensin-(1–7) [Ang-(1–7)]. Patients with AD also have reduced numbers of functional circulating angiogenic cells, perhaps reflecting diminished progenitor reserves. However, the role of these angiogenic cells early in cognitive decline is unknown. This dissertation consists of two main parts: (1) a preclinical study investigating the efficacy of the ARB candesartan and Ang-(1–7) in an animal model of AD and (2) an observational clinical study of circulating angiogenic cells in older adults with mild cognitive impairment (MCI). ❧ Methods: In the preclinical study, triple transgenic AD (3xTg-AD) mice were treated with candesartan, Ang-(1–7), or both for 8 months. Hippocampal amyloid-beta (Aβ) was assessed by immunoassay, and potential underlying mechanisms were investigated including: endothelial progenitor cells (EPCs), carotid blood flow, and Aβ clearance pathways. In the clinical study, adults (55 years of age or older) underwent a neuropsychological exam, MRI brain scan, and blood draw. Circulating angiogenic cells were characterized by flow cytometry and colony-forming assay. ❧ Results: 3xTg-AD mice treated with candesartan and Ang-(1–7) showed significant reductions in hippocampal insoluble Aβ. Candesartan increased circulating EPCs, reduced carotid blood flow, and increased the mRNA expression of Aβ-degrading enzymes insulin-degrading enzyme (IDE) and endothelin-converting enzyme 2 (ECE2), and microglial activation markers CD45 and Iba1. Participants with MCI exhibited significantly reduced progenitor cell subsets CD34 and CD133. Angiogenic cell subsets positively correlated with performance on verbal and visual memory tests. Voxel-wise regression analyses revealed that participants with higher CD34 cells correlated to increased volumes in the lingual gyrus, posterior cingulate gyrus, and precuneus. ❧ Conclusion: Long-term treatment with candesartan and Ang-(1–7) significantly reduced hippocampal Aβ in a mouse model of AD, which may be attributed to increased Aβ clearance potentially through the increased expression of Aβ-degrading enzymes IDE and ECE2. Circulating progenitor cells were found to be decreased in MCI, and positively correlated to memory tests and brain regions involved in verbal and visual memory. These results suggest that circulating progenitor cells may have a protective role in the early stages of cognitive decline, which may serve as a useful diagnostic, biomarker, or point of intervention