Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid β-protein metabolism in mouse models of Alzheimer disease

Hemming, Matthew L.; Selkoe, Dennis J.; Farris, Wesley

doi:10.1016/j.nbd.2007.01.004

Cited by 102 publications

(79 citation statements)

References 44 publications

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“…Here, it was entirely appropriate to test ACE inhibitors in animal models of AD. In this particular case, several independent studies failed to show any effect of ACE inhibitors on A␤ accumulation (39,40). Together with other findings from knock-out animals (39), these pharmacological studies were instrumental in establishing that ACE is not important for A␤ degradation in vivo (at least in rodents).…”

Section: Categories Of Investigationmentioning

confidence: 79%

The AβCs of Aβ-cleaving Proteases

Leissring

2008

Journal of Biological Chemistry

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The amyloid ␤-protein (A␤), which accumulates abnormally in Alzheimer disease (AD), is degraded by a diverse set of proteolytic enzymes. A␤-cleaving proteases, largely ignored until only recently, are now known to play a pivotal role in the regulation of cerebral A␤ levels and amyloid plaque formation in animal models, and accumulating evidence suggests that defective A␤ proteolysis may be operative in many AD cases. This review summarizes the growing body of evidence supporting the involvement of specific A␤-cleaving proteases in the etiology and potential treatment of AD. Recognition of the importance of A␤ degradation to the overall economy of A␤ has revised our thinking about the mechanistic basis of AD pathogenesis and identified a novel class of enzymes that may serve as both therapeutic targets and therapeutic agents.

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Section: Categories Of Investigationmentioning

confidence: 79%

The AβCs of Aβ-cleaving Proteases

Leissring

2008

Journal of Biological Chemistry

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“…At present, the balance of the evidence suggests that it is not. Oral administration of the widely used ACE inhibitor, captopril, to APP transgenic mice resulted in no significant elevation in cerebral Ab levels (Hemming et al 2007b). Moreover, genetic deletion of ACE failed to produce any significant elevation in steady-state levels of endogenous Ab (Table 1; Eckman et al 2006).…”

Section: Angiotensin-converting Enzymementioning

confidence: 99%

Proteolytic Degradation of Amyloid -Protein

Saido

Leissring²

2012

Cold Spring Harbor Perspectives in Medicine

305

269

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The amyloid b-protein (Ab) is subject to proteolytic degradation by a diverse array of peptidases and proteinases, known collectively as Ab-degrading proteases (AbDPs). A growing number of AbDPs have been identified, which, under physiological and/or pathophysiological conditions, contribute significantly to the determination of endogenous cerebral Ab levels. Despite more than a decade of investigation, the complete set of AbDPs remains to be established, and our understanding of even well-established AbDPs is incomplete. Nevertheless, the study of known AbDPs has contributed importantly to our understanding of the molecular pathogenesis of Alzheimer disease (AD) and has inspired the development of several novel therapeutic approaches to the regulation of cerebral Ab levels. In this article, we discuss the general features of Ab degradation and introduce the best-characterized AbDPs, focusing on their diverse properties and the numerous conceptual insights that have emerged from the study of each.

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“…ACE was also expressed in the brain by resident CD45 lo-intermed ACE hi microglia. In AD + ACE 10 risk (20,(64)(65)(66)(67). Several meta-analyses have consistently found that lower serum and tissue ACE levels, as determined by an ACE gene polymorphism, were associated with a small increased risk of developing AD (68)(69)(70)(71).…”

Section: Figurementioning

confidence: 99%

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

Bernstein¹,

Koronyo²,

Salumbides³

et al. 2014

J. Clin. Invest.

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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.

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Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid β-protein metabolism in mouse models of Alzheimer disease

Cited by 102 publications

References 44 publications

The AβCs of Aβ-cleaving Proteases

The AβCs of Aβ-cleaving Proteases

Proteolytic Degradation of Amyloid -Protein

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

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