Angiofensin converting enzyme density is increased in temporal cortex from patients with Alzheimer's disease

Barnes, Nicholas M.; Cheng, Celine H.K.; Costall, B.; Naylor, R.J.; Williams, Timothy J.; Wischik, C. M.

doi:10.1016/0014-2999(91)90584-d

Cited by 126 publications

(78 citation statements)

References 18 publications

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“…On the other hand, it can be postulated that increases in the levels of Aβ in the brain of AD patients might trigger increased expression of ACE in the brain. Regarding evidences that ACE is up-regulated in AD patients, [45][46][47] it could be suggested that brain ACE may enter into the blood circulation and consequently would increase the ACE level in blood of AD patients. 37 Last but not least, correlations between ACE levels and AD may relate more to the effects on the renin-angiotensin system and brain vascular changes than to a major contribution to Aβ clearance.…”

Section: Discussionmentioning

confidence: 99%

Serum concentration of beta amyloid peptide and the activity of angiotensin converting enzyme in alzheimers disease patients: search for a potential biomarker

2016

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Section: Discussionmentioning

confidence: 99%

Serum concentration of beta amyloid peptide and the activity of angiotensin converting enzyme in alzheimers disease patients: search for a potential biomarker

2016

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“…Post-mortem studies of patients with AD have found elevated levels of ACE in the temporal cortex and specifically within pyramidal cortical neurons (27,28) as well as significantly increased ACE activity in the medial hippocampus, parahippocampal gyrus, frontal cortex, and caudate nucleus (29). A mechanistic link between ACE and AD was suggested when affinity-purified ACE was shown to degrade synthetic A␤- between the Asp 7 -Ser 8 bond in vitro, producing a truncated 33-residue peptide that exhibited decreased aggregation and cytotoxic potential (30).…”

mentioning

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

288

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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“…In fact, studies (Hirawa et al, 1999;Savaskan et al, 2001;Ohrui et al, 2004) have reported elevated levels of ACE in the hippocampus, parahippocampal gyrus, frontal cortex, and caudate nucleus of AD patients. The increased ACE activity may be directly responsible for cognitive impairment in AD because the enhanced formation of angiotensin II would result in an increased inhibitory effect on acethylcholine release (Barnes et al, 1991). On the same line Sudilovsky et al (1987) suggest that ACE may have a role in the modulation of cognitive memory processes in rat and in humans.…”

Section: Discussionmentioning

confidence: 96%

Effects of cholinesterase inhibitors appear greater in patients on established antihypertensive therapy

Rozzini

Chilovi

Bellelli

et al. 2005

Int J Geriat Psychiatry

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SUMMARYIntroduction There is increasing evidence that hypertension may contribute to development of dementia. Studies show that blood pressure lowering therapy might protect against cognitive deterioration and that antihypertensive treatment reduce the incidence of dementia. Aim We hypothesize that administration of cholinesterase inhibitors (AChEis) to patients with Alzheimer's Disease (AD) receiving antihypertensive medications therapy would result in clinical benefits for a period of 40 weeks in routine clinical practice. Methods and materials Patients with possible or probable AD were enrolled from 16 Alzheimer evaluation units (UVA) of Brescia and Cremona (Northern Italy). Patients treated with donepezil, rivastigmine and galantamine for 40 weeks independently of dosages were selected. Patients were evaluated at baseline (T0), 4 weeks (T1), 16 weeks (T2) and 40 weeks (T3). Results 416 patients completed the study at 40 weeks; of these 255 were 'non users' while 161 utilized antihypertensive drugs ('users'). The mean change in MMSE score from baseline to week 40 demonstrate that antihypertensive-treated patients improved by 0.7 points while patients receiving only AChEis remain stables. Analyzing separately patients (n ¼ 183) that ameliorate (responders) on cognition at T3 ( ! 1 point MMSE score increase) a significant differences in favor of 'users' antihypertensive drugs over 'non users' on cognition at weeks 16 and 40 has been demonstrated. In particular, at T2 the mean change of MMSE from baseline in 'users' was 3.2 AE 2.6 vs 'non users' 2.2 AE 2.3 ( p ¼ 0.016) and at T3 was 3.5 AE 2.5 vs 'non users' 2.0.2.7 AE 1.6 ( p ¼ 0.018). Antihypertensive drugs were independently associated with cognitive improvement in responder patients treated with AChEis (95% CI: 0.41-1.79; p ¼ 0.002). Conclusion Antihypertensive medications in AD patients treated with AChEis are associated with an independent improvement on cognition after 40 weeks of treatment.

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Angiofensin converting enzyme density is increased in temporal cortex from patients with Alzheimer's disease

Cited by 126 publications

References 18 publications

Serum concentration of beta amyloid peptide and the activity of angiotensin converting enzyme in alzheimers disease patients: search for a potential biomarker

Serum concentration of beta amyloid peptide and the activity of angiotensin converting enzyme in alzheimers disease patients: search for a potential biomarker

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

Effects of cholinesterase inhibitors appear greater in patients on established antihypertensive therapy

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