Angiotensin Converting Enzyme in Alzheimer's Disease: Increased Activity in Caudate Nucleus and Cortical Areas

Arregui, Alberto; Perry, Elaine K.; Rossor, Martin N.; Tomlinson, Bernard E.

doi:10.1111/j.1471-4159.1982.tb07930.x

Cited by 141 publications

(85 citation statements)

References 25 publications

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“…Data from histopathological studies indicate a major overlap between vascular lesions and AD (Arregui et al 1982;Victoroff et al 1995;Snowdon et al 1997). By promoting arteriosclerosis and lipohyalinosis of the small vessels, hypertension might be the origin of stroke and/or chronic hypoperfusion of the white matter, thus contributing to the early expression of a still subclinical AD.…”

Section: Hypertension and Cognitive Declinementioning

confidence: 99%

Vascular risk factors, cognitve decline, and dementia

Duron

Hanon²

2008

VHRM

250

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Dementia is one of the most important neurological disorders in the elderly. Aging is associated with a large increase in the prevalence and incidence of degenerative (Alzheimer's disease) and vascular dementia, leading to a devastating loss of autonomy. In view of the increasing longevity of populations worldwide, prevention of dementia has turned into a major public health challenge. In the past decade, several vascular risk factors have been found to be associated with vascular dementia but also Alzheimer's disease. Some longitudinal studies, have found signifi cant associations between hypertension, diabetus mellitus, and metabolic syndrome, assessed at middle age, and dementia. Studies assessing the link between hypercholesterolemia, atrial fi brillation, smoking, and dementia have given more confl icting results. Furthermore, some studies have highlighted the possible protective effect of antihypertensive therapy on cognition and some trials are evaluating the effects of statins and treatments for insulin resistance. Vascular risk factors and their treatments are a promising avenue of research for prevention of dementia, and further long-term, placebo-controlled, randomized studies, need to be performed.

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Section: Hypertension and Cognitive Declinementioning

confidence: 99%

Vascular risk factors, cognitve decline, and dementia

Duron

Hanon²

2008

VHRM

250

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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

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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“…Так, выявлена положительная корреляция между увеличением в мозге нейрональной и периваскулярной активности АПФ и отложением Аb в виде сенильных бляшек в паренхиме и кровяных сосудах мозга, а также стадиями болезни [5,23,89,90,91]. Судя по данным посмертных исследований, уровень активности АПФ повышен в срединном гиппокампе, парагиппокампальной извилине, хвостатом ядре, входящем в состав полосатого тела и коре головного мозга [93][94][95]. Существенное увеличение АТ 1 Р и АТ 2 Р, ассоциированное с БА, обнаружено в коре головного мозга [93,96].…”

Section: ангиотензин превращающий фермент и болезнь альцгеймераunclassified

Angiotensin converting enzyme and Alzheimer's disease

Кугаевская

2013

BIOMED KHIM

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Болезнь Альцгеймера (БА) -неизлечимое дегенеративное заболевание центральной нервной системы, приводящее к деменции. В основе БА лежит нейродегенеративный процесс, приводящий к гибели нейронов коры головного мозга, связанный с образованием в мозге нейрофибриллярных клубков и отложением сенильных или амилоидных бляшек, главным компонентом которых является пептид бета-амилоид (Аb). Факторами риска развития БА являются возраст, а также гипертензия, атеросклероз, диабет и гиперхолестеринемия, в патогенез которых вовлечен ангиотензин превращающий фермент (АПФ), ключевой фермент ренин-ангиотензиновой (РАС) и калликреин-кининовой (ККС) систем. Недавно было обнаружено, что АПФ, наряду с другими металлопротеиназами, принимает участие в метаболизме Аb, расщепляя связи на N-концевом и С-концевом участках молекулы Аb. Интерес к роли АПФ в процессах деградации Аb связан с тем, что назначение ингибиторов АПФ (иАПФ) является основным терапевтическим подходом, применяемым при лечении различных форм гипертонии и других сердечно-сосудистых заболеваний. Однако до сих пор не решен вопрос о том, могут ли применяться антигипертензивные препараты, тормозящие РАС, для лечения или предупреждения БА. В настоящее время проводятся многочисленные исследования, посвященные поиску взаимосвязи между РАС и БА.Ключевые слова: болезнь Альцгеймера, пептид бета-амилоид, ангиотензин превращающий фермент, ингибиторы ангиотензин превращающего фермента.ВВЕДЕНИЕ. Болезнь Альцгеймера (БА) -один из наиболее распространенных случаев деменции, составляющий 50-60% от общего числа заболевших. Основным фактором риска развития БА является возраст. Число заболевших существенно растет после 65 лет и приближается к 50% среди людей, достигших 85 лет [1]. Хотя традиционно БА рассматривается 5

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Angiotensin Converting Enzyme in Alzheimer's Disease: Increased Activity in Caudate Nucleus and Cortical Areas

Cited by 141 publications

References 25 publications

Vascular risk factors, cognitve decline, and dementia

Vascular risk factors, cognitve decline, and dementia

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

Angiotensin converting enzyme and Alzheimer's disease

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