Angiotensin-converting enzyme overexpression in mouse neutrophils prevents Alzheimer's-like cognitive decline

Angiotensin-converting enzyme (ACE), a dipeptidyl carboxypeptidase, is known to cleave amyloid-beta (Aβ), and its reduced activity has been linked to the progression of Alzheimer's disease (AD). Our research indicates that ACE is vital for myeloid cell functions. Using ACE10/10 recombinant mice, we demonstrated that overexpressing ACE in macrophages mitigates AD pathology in these mice. Given that neutrophils are the most abundant white blood cells, this study investigates whether ACE overexpression in neutrophils influences AD progression. We crossed NeuACE mice, which overexpress ACE in neutrophils, with 3xTg-AD mice to create AD-NeuACE mice. Behavioral changes and brain pathology were assessed through various behavioral mazes and histological assays. AD-NeuACE mice demonstrated improved cognitive functions and lower Aβ levels in the cortex and hippocampus compared to AD mice. In-vitro data indicate that ACE-overexpressing neutrophils are significantly more effective at phagocytosing and clearing Aβ fluorescence particles. This study suggests that overexpressing ACE in neutrophils could be a promising approach to managing AD-like phenotypes.