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 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(ΔE9) 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.
Kenneth E
KE
Bernstein
Yosef
Y
Koronyo
Brenda C
BC
Salumbides
Julia
J
Sheyn
Lindsey
L
Pelissier
Dahabada H J
DH
Lopes
Kandarp H
KH
Shah
Ellen A
EA
Bernstein
Dieu-Trang
DT
Fuchs
Jeff J-Y
JJ
Yu
Michael
M
Pham
Keith L
KL
Black
Xiao Z
XZ
Shen
Sebastien
S
Fuchs
Maya
M
Koronyo-Hamaoui
D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D002465:Cell Movement; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D003071:Cognition; D005260:Female; D006801:Humans; D008264:Macrophages / Q000502:physiology; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000201:enzymology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D017257:Ramipril / Q000494:pharmacology; D012995:Solubility
D016229:Amyloid beta-Peptides; D000806:Angiotensin-Converting Enzyme Inhibitors; D007703:Peptidyl-Dipeptidase A; D017257:Ramipril