Targeted angiotensin converting enzyme over‐expression in myelomonocytes prevents cognitive decline in Alzheimer’s‐like disease (153.3)

Abstract

The cognitive decline in Alzheimer's disease (AD) is associated with elevated brain levels of amyloid β‐protein (Aβ), particularly Aβ1‐42. Angiotensin‐converting enzyme (ACE) can enzymatically degrade Aβ1‐42 and its overexpression in myelomonocytic cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACE10/10 mice, which over express ACE in myelomonocytic cells, with the double‐transgenic APPSWE/PS1ΔE9 mouse model of AD (AD+). At 7 months, soluble Aβ1‐42 was reduced by 44% (136 vs 245 pg/mg) and Aβ1‐40 was reduced by 32% (21 vs 31 pg/mg). Plaque burden was reduced by as much as 79% (13 vs 62 103mm2) and insoluble Aβ1‐42 by 64% (189 vs 521 pg/mg). There was also a substantial reduction in astrogliosis (49‐57% at 7 months, 50% at 13 months). AD+ACE10/10 mice demonstrated less overall brain infiltrating cells, consistent with less AD pathology, though ACE‐overexpressing monocytes and macrophages were increasingly abundant surrounding and engulfing Aβ plaque. At 11 and 12 months, AD+ACE10/WT and AD+ACE10/10 mice were virtually equivalent to non‐AD mice in cognitive ability as assessed by maze‐based behavioral tests. This study shows that an enhanced immune response, coupled with increased myelomonocytic cell expression of ACE, resulted in essentially complete prevention of the cognitive decline observed in a murine model of AD.Grant Funding Source: Supported by HL088000, HL110353, and the C.A.R.T fund, UL1TR000124,