| First Author | Bernstein KE | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 3 | Pages | 1000-12 |
| PubMed ID | 24487585 | Mgi Jnum | J:209432 |
| Mgi Id | MGI:5567858 | Doi | 10.1172/JCI66541 |
| Citation | Bernstein KE, et al. (2014) Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer's-like cognitive decline. J Clin Invest 124(3):1000-12 |
| abstractText | Cognitive decline in patients with Alzheimer's disease (AD) is associated with elevated brain levels of amyloid beta protein (Abeta), particularly neurotoxic Abeta(1-42). Angiotensin-converting enzyme (ACE) can degrade Abeta(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(DeltaE9) 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 Abeta(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 Abeta 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 Abeta 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. |
