ACE I/D polymorphism is a risk factor of Alzheimer's disease but not of vascular dementia

Kölsch, Heike; Jessen, Frank; Freymann, Nikolaus; Kreis, M.; Hentschel, Frank; Maier, Wolfgang; Heun, Reinhard

doi:10.1016/j.neulet.2004.11.062

Cited by 64 publications

(49 citation statements)

References 18 publications

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“…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). On the other hand, recent genomewide association studies have failed to find involvement of ACE genetic variation in AD (64,72).…”

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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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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“…Of potential mechanistic relevance, inheritance of the D allele has been associated with increased plasma ACE levels (22). Regarding disease specificity, the I allele has been found to associate positively with AD but not with vascular dementia or vascular pathology (23,24). The I/I genotype has also been linked to smaller volumes of the hippocampus and the amygdala (24).…”

Section: An Early and Pathogenically Important Feature Of Alzheimer Dmentioning

confidence: 99%

Amyloid β-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor

Hemming

Selkoe

2005

Journal of Biological Chemistry

295

211

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Human genetic data have associated angiotensin-converting enzyme (ACE) with Alzheimer disease (AD), and purified ACE has been reported to cleave synthetic amyloid ␤-protein (A␤) in vitro. Whether deficiency in ACE activity, arising from genetic alteration or pharmacological inhibition, can decrease A␤ degradation and allow A␤ accumulation in intact cells is unknown. We cloned ACE from human neuroblastoma cells and showed that it had posttranslational processing and enzymatic activity typical of the endogenous protease. Cellular expression of ACE promoted degradation of naturally secreted A␤40 and A␤42, leading to significant clearance of both species. Using site-directed mutagenesis, we determined that both active sites within ACE contribute to A␤ clearance, and an ACE construct bearing mutations in each catalytic domain had no effect on A␤ levels. Pharmacological inhibition of ACE with a widely prescribed drug, captopril, promoted the accumulation of cell-derived A␤ in the media of ␤-amyloid precursor-protein expressing cells. Together, these results show that ACE can lower the levels of secreted A␤ in living cells and that this effect is blocked by inhibiting the protease's activity with an ACE inhibitor. This work, combined with the genetic studies, supports the hypothesis that ACE may modulate the susceptibility to and progression of AD via degradation of A␤. Our data encourage further analyses of the ACE gene for disease association and raise the question of whether currently prescribed ACE inhibitors could elevate cerebral A␤ levels in humans. An early and pathogenically important feature of Alzheimer disease (AD)2 is the progressive accumulation and deposition of the amyloid ␤-protein (A␤) in brain regions serving memory and cognition. Biochemical, cell biological, animal modeling, genetic, and emerging clinical data all suggest that A␤ is an upstream initiator of the disease process and its associated neuropathology (1-4). Although no proven diseasemodifying treatments are currently available, recent efforts to treat AD have focused on both decreasing the production of A␤ and enhancing its clearance from the brain. One little studied approach to A␤ clearance is augmenting the degradation of the peptide by various proteases expressed in the brain. Thus far, the metalloproteases neprilysin (NEP) (5), insulin-degrading enzyme (IDE) (6), and the endothelin-converting enzymes 1 and 2 (7) have each been implicated as A␤-degrading proteases in the mammalian brain. The serine protease plasmin has been implicated in A␤ degradation in vitro (8), although genetic plasmin deficiency did not promote accumulation of murine A␤ in vivo (9). Supporting a role for therapeutic regulation of A␤-degrading proteases, the overexpression of IDE or NEP in a murine model of AD decreased cerebral A␤ levels and produced significant attenuation of A␤-associated neuropathology (10).Somatic angiotensin-converting enzyme (ACE) is a zinc metalloprotease containing two homologous regions, termed the N-and C-domains, each of which is prot...

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“…A link between ACE and AD was first hypothesized by human genetic studies, which have found both single nucleotide polymorphisms (Katzov et al, 2004) and an intronic insertion (I)/deletion (D) polymorphism within the ACE gene that associate with AD (Lehmann et al, 2005). The I allele has been associated with an increased risk for AD, but not for vascular dementia (Kolsch et al, 2005). The D allele is associated with reduced risk for AD, and carriers of this protective allele have elevated levels of the ACE protein (Rigat et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

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

Hemming

Selkoe

Farris

2007

Neurobiology of Disease

102

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Genetic and pathologic studies have associated angiotensin-converting enzyme (ACE) with Alzheimer disease. Previously, we and others have reported that ACE degrades in vitro the amyloid β-protein (Aβ), a putative upstream initiator of Alzheimer disease. These studies support the hypothesis that deficiency in ACE-mediated Aβ proteolysis could increase Alzheimer disease risk, and raise the question of whether ACE inhibitors, a commonly prescribed class of anti-hypertensive medications, can elevate Aβ levels in vivo. To test this hypothesis, we administered the ACE inhibitor captopril to two lines of APP transgenic mice harboring either low levels of Aβ or high levels of Aβ with associated plaque deposition. In both models, we show that captopril does not affect cerebral Aβ levels in either soluble or insoluble pools. Further, we find no change in plaque deposition or in peripheral Aβ levels. Data from these Alzheimer models suggest that captopril and similar ACE inhibitors do not cause Aβ accumulation in vivo.

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ACE I/D polymorphism is a risk factor of Alzheimer's disease but not of vascular dementia

Cited by 64 publications

References 18 publications

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

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

Amyloid β-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor

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

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