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

摘要

Cognitive decline in patients with Alzheimer’s disease (AD) is associated with elevated brain levels of amyloid β protein (Aβ), particularly neurotoxic Aβ_(1–42). Angiotensin-converting enzyme (ACE) can degrade Aβ_(1–42), and ACE overexpression in myelomonocytic cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACE~(10/10) mice, which overexpress ACE in myelomonocytes using the c-fms promoter, with the transgenic APP_(SWE)/PS1 _(Δ 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 Aβ_(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 Aβ 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 Aβ plaques. At 11 and 12 months of age, the AD~(+)ACE~(10/WT) and AD~(+)ACE~(10/10) 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 myelomonocytic expression of catalytically active ACE, prevents cognitive decline in a murine model of AD.