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A? degradation or cerebral perfusion? Divergent effects of multifunctional enzymes.

ABSTRACT: There is increasing evidence that deficient clearance of ?-amyloid (A?) contributes to its accumulation in late-onset Alzheimer disease (AD). Several A?-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), and angiotensin-converting enzyme (ACE) reduce A? levels and protect against cognitive impairment in mouse models of AD. In post-mortem human brain tissue we have found that the activity of these A?-degrading enzymes rise with age and increases still further in AD, perhaps as a physiological response that helps to minimize the build-up of A?. ECE-1/-2 and ACE are also rate-limiting enzymes in the production of endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictors, increases in the levels of which are likely to contribute to reduced blood flow in AD. This review considers the possible interdependence between A?-degrading enzymes, ischemia and A? in AD: ischemia has been shown to increase A? production both in vitro and in vivo, whereas increased A? probably enhances ischemia by vasoconstriction, mediated at least in part by increased ECE and ACE activity. In contrast, NEP activity may help to maintain cerebral perfusion, by reducing the accumulation of A? in cerebral blood vessels and lessening its toxicity to vascular smooth muscle cells. In assessing the role of A?-degrading proteases in the pathogenesis of AD and, particularly, their potential as therapeutic agents, it is important to bear in mind the multifunctional nature of these enzymes and to consider their effects on other substrates and pathways.

SUBMITTER: Miners JS

PROVIDER: S-EPMC4160973 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Aβ degradation or cerebral perfusion? Divergent effects of multifunctional enzymes.

Miners J Scott JS Palmer Jennifer C JC Tayler Hannah H Palmer Laura E LE Ashby Emma E Kehoe Patrick G PG Love Seth S

Frontiers in aging neuroscience 20140911

There is increasing evidence that deficient clearance of β-amyloid (Aβ) contributes to its accumulation in late-onset Alzheimer disease (AD). Several Aβ-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), and angiotensin-converting enzyme (ACE) reduce Aβ levels and protect against cognitive impairment in mouse models of AD. In post-mortem human brain tissue we have found that the activity of these Aβ-degrading enzymes rise with age and increases still further in AD ...[more]

PMID: 25309424

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Project description:BackgroundCerebral hypoperfusion and impaired oxygen delivery during pediatric critical illness may result in acute neurologic injury with subsequent long-term effects on neurodevelopmental outcome. Yet, the impact of norepinephrine on cerebral hemodynamics is unknown in children with shock. We aimed to describe the norepinephrine effects on cerebral perfusion and oxygenation during pediatric shock.Patients and methodsWe conducted an observational multicentre prospective study in 3 French pediatric intensive care units. Children <18 years of age excluding traumatic brain injury were included in the study if they need norepinephrine for shock. Systemic and cerebral hemodynamics were compared between the time of initiation of norepinephrine (T0), and the steady-state (Tss). Cardiac output (CO) was measured using ultrasound. Cerebral perfusion was assessed on middle cerebral arteries (MCA) using transcranial doppler ultrasound. Cerebral tissue oxygen saturation (rScO2) was recorded using near infrared spectroscopy, and we calculated cerebral fractional tissue oxygen extraction (cFTOE = SpO2-rScO2/SpO2).Main resultsFourteen children (median [IQR] age of 3.5[1; 13.5] years) were included. Norepinephrine at 0.2[0.1; 0.32] μg/kg/min significantly increased mean arterial blood pressure (61[56; 73] mmHg at Tss vs. 49[42;54] mmHg at T0, p=10-3) without change of CO. MCA velocities, pulsatility index, rScO2, and cFTOE did not significantly change between T0 and Tss. Some individuals observed variations in estimated CBF, which slightly improved in 7 patients, remained unchanged in 5, and was impaired in 2. No patient experienced significant variations of rScO2.ConclusionsLow-dosing norepinephrine, despite a homogeneous and significant increase in arterial blood pressure, had little effects on cerebral perfusion and oxygenation during pediatric shock. This reinforces the need for personalized tailored therapies in this population.Trial registrationClinicaltrials.gov, NCT03731104. Registered 6 November, 2018. https://clinicaltrials.gov/ct2/show/NCT03731104.

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A? degradation or cerebral perfusion? Divergent effects of multifunctional enzymes.

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Aβ degradation or cerebral perfusion? Divergent effects of multifunctional enzymes.

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