Abstract 59: Targeted Angiotensin Converting Enzyme Overexpression in Myelomonocytic Cells Prevents Cognitive Decline in Alzheimer’s Disease

Abstract

The cognitive decline in Alzheimer's disease (AD) is associated with elevated brain levels of amyloid β-protein (Aβ), particularly Aβ 1-42 . Angiotensin-converting enzyme (ACE) can enzymatically degrade Aβ 1-42 and its 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 over express ACE in myelomonocytic cells, with the double-transgenic APP SWE /PS1 ΔE9 mouse model of AD (AD + ). At 7 months, soluble Aβ 1-42 was reduced by 44% (136 vs 245 pg/mg) and Aβ 1-40 was reduced by 32% (21 vs 31 pg/mg). Plaque burden was reduced by as much as 79% (13 vs 62 10 3 mm 2 ) and insoluble Aβ 1-42 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 + ACE 10/10 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 + 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. 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.

Angiotensin Converting Enzyme (ACE) expression in microglia reduces amyloid β deposition and neurodegeneration by increasing SYK signaling and endolysosomal trafficking

“…By contrast, ACE 10/10 mice that express ACE in peripheral myelomonocytes (and microglia -Fig. S1) have reduced Aβ deposition, neurodegeneration and improved learning and memory deficits when crossed to the APP/PS1 Aβ producing mice (31). Here, we found that selective expression of ACE in microglia/CAMs potentiates their ability to process Aβ.…”

“…Overexpression of ACE in myelomonocytes which included microglia in the APP/PS1 amyloid mouse model, decreased amyloid plaque formation and improved learning and memory that were dependent on ACE catalytic activity, but independent of blood pressure regulation (31).…”

Myeloid cell ACE shapes cellular metabolism and function in PCSK-9 induced atherosclerosis

“…This enhancement ultimately reduces the formation of atherosclerotic plaques in adenoassociated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-induced atherosclerosis in ACE10/10 mice (7,8). We further showed that ACE 10/10 macrophages stimulate abundant ATP production dependent on Kreb's cycle intermediates compared with WT cells (9)(10)(11)(12). Hence, our findings suggest that the upregulation of ACE may positively enhance metabolic reactions in macrophages, which ultimately provides a protective effect in atherosclerosis.…”

“…For instance, the immunopathogenesis of Alzheimer's disease (AD) contains failing lipid handling and metabolism of brain microglia which possess similar differentiation origin and functional character with peripheral macrophage. In fact, we have already found that ACE10/10 mice showed highly resistant character in the AD model (9,10). We revealed that ACE10/10 microglia captured and degraded amyloid beta (Ab) as one of the potential benefits to attenuate AD symptom; however, there is a possibility that lipid metabolism is enhanced by ACE overexpression in the microglia.…”