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

Cognitive decline in patients with Alzheimer's disease (AD) is associated with elevated brain levels of am.yloid beta protein (A beta), particularly neurotoxic A beta(1-42). Angiotensin-converting enzyme (ACE) can degrade A beta(1-42), and ACE overexpression in myelomonocydc cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACEW mice, which overexpress ACE in myelomonocytes using the c-fins promoter, with the transgenic APP(SWE)/PS1(Delta E9) mouse model of AD (AD). Evaluation of brain tissue from these AD ACE(10/10)- mice at 7 and 13 months revealed that levels of both soluble and insoluble brain A beta(1-42) were reduced compared with those in AD(+) mice. Furthermore, both plaque burden and astrogliosis were drastically reduced. Administration of the ACE inhibitor ramipril increased A beta levels in AD(+)ACE(10/10) mice compared with the levels induced by the ACE-independent vasodilator hydralazine. Overall, AD+ACE(10/10) mice had less brain-infiltrating cells, consistent with reduced AD-associated pathology, though ACE-overexpressing macrophages were abundant around and engulfing A beta plaques. At 11 and 12 months of age, the AD'ACEnVwT and AD AcElop.o mice were virtually equivalent to non-AD mice in cognitive ability, as assessed by maze-based behavioral tests. Our data demonstrate that an enhanced immune response, coupled with increased myelomonocydc expression of catalytically active ACE, prevents cognitive decline in a murine model of AD.