P3‐348: Targeted high‐expression of ACE to myelomonocytic cells diminishes Alzheimer's‐like pathology and restores memory and learning in mouse models

Background: Previous studies from our group and others have demonstrated that peripheral immune cells and especially infiltrating bloodborne monocytes can home to pathological beta-amyloid protein aggregates (Ab plaques) and facilitate their clearance by phagocytosis and secretion of Ab-degrading enzymes. One of the enzymes that was shown capable of degrading Ab and convert the deleterious Ab (1-42) to shorter nontoxic isoforms is angiotensin-converting enzyme (ACE). Results: We found a marked reduction in Ab plaque number and size in the cortex and hippocampus of 5, 7 and 12 month-old AD mice; above 40% decrease in mice having one ACE10 allele and above 80% in mice having two ACE10 alleles. Moreover, the levels of soluble neurotoxic Ab (1-42) isoforms were substantially decreased in brain and plasma of ACE10xADtg mice. Importantly, ADtg mice carrying either one or two ACE10 alleles had a considerable improvement in learning and memory functions as assessed by a panel of behavioral tests such as the Barnes maze, and were indistinguishable than the wild type non-AD mice. These effects were accompanied by an extensive reduction in cortical astrogliosis as assessed by number and area of reactive GFAP-positive astrocytes. Flow cytometry analysis of immune cell profiles in the brain revealed a significant increase in migration of ACE10-overexpessing monocytes as compared to wt monocytes in ADtg mice. Conclusions: These studies indicate that selective ACE-overexpression in microglia and monocytes leads to a remarkable attenuation of AD-like progression in mouse models. Therefore, targeted overexpression of ACE on monocytes may present a highly promising and novel disease-modifying approach for AD treatment.