A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice

Abstract

Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic β-amyloid protein 42 (Aβ42) to Aβ40. Because of its neurotoxicity, Aβ42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aβ40 has neuroprotective effects against Aβ42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aβ42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aβ42-to-Aβ40–converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE+/− mice and found that a decrease in ACE levels promoted Aβ42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.

The use of angiotensin-converting enzyme inhibitors vs. angiotensin receptor blockers and cognitive decline in Alzheimer’s disease: the importance of blood-brain barrier penetration and APOE ε4 carrier status

“…Moreover, a neuropathology study found that ARBs were associated with reduced Aβ plaque load, and a cross-sectional PET study yielded similar results with PiB binding [32,33]. It has been suggested that preservation of angiotensin-converting enzyme-1 (ACE-1) function by ARBs, but not ACE-Is, may explain this difference, as ACE-1 has demonstrated a role in the prevention of Aβ aggregation and fibril formation in vitro [74,75], although results from animal models have been highly variable [76][77][78][79][80].…”

The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma

“…Despite a complex protease web for ACE, clinical applications of ACE inhibitors have existed for decades. A recent concern has arisen based on ACE inhibition resulting in increased brain amyloid deposition and apoptotic neurons in mice [93]. Whether this translates to human disease remains to be seen.…”

Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits

“…Other studies have found evidence that patients taking ACE inhibitors have decreased cognitive function and increased levels of β-amyloid (Aβ) protein in their central nervous system; these results were also replicated in mice [40]. This is thought to be due to ACE's ability to cleave Aβ42 to Aβ40, which is a form of Aβ that is less pathogenic than Aβ42 due to it being less prone to aggregate in the brain [40]. Increases in Aβ42 to Aβ40 ratios have been associated with the PSEN1 and PSEN2 mutations in the familial form of AD [44].…”

“…Several studies have found that patients on ACE inhibitors that cross the blood-brain barrier (centrally acting) are at reduced risk of dementia and have improved cognitive ability. Other studies have found evidence that patients taking ACE inhibitors have decreased cognitive function and increased levels of β-amyloid (Aβ) protein in their central nervous system; these results were also replicated in mice [40]. This is thought to be due to ACE's ability to cleave Aβ42 to Aβ40, which is a form of Aβ that is less pathogenic than Aβ42 due to it being less prone to aggregate in the brain [40].…”

“…Three of the pleiotropic loci we report implicate blood pressure mechanisms involved in the pleiotropic relationship at the locus, and four loci had candidate causal genes that have been shown to be involved in immune responses. While these mechanisms make sense given that hypertension and inflammation have both been linked with AD and cardiometabolic diseases, they have not been prevalent in the discussion of pleiotropy between these traits [4,34,[39][40][41][42]. We did not perform experiments to identify causal variants at these loci in this study.…”