THE ROLE OF CYSTEINE PROTEASE IN ALZHEIMER DISEASE

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Abstract

Introduction:

Cysteine protease are biological catalysts which play a pivotal role in numerous biological reactions in organism. Much of the literature is inscribed to their biochemical significance, distribution and mechanism of action. Many diseases, e.g. Alzheimer’s disease, develop due to enzyme balance disruption. Understanding of cysteine protease’s disbalance is therefor a key to unravel the new possibilities of treatment. Cysteine protease are one of the most important enzymes for protein disruption during programmed cell death. Whether protein disruption is part of cell deaths is not enough clear in any cases. Thereafter, any tissue disruption, including proteolysis, generate more or less inflammation appearance.

Review:

This review briefly summarizes the current knowledge about pathological mechanism’s that results in AD, with significant reference to the role of cysteine protease in it. Based on the summary, new pharmacological approach and development of novel potent drugs with selective toxicity targeting cysteine protease will be a major challenge in years to come.

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Most cited references 37

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Alzheimer disease in the US population: prevalence estimates using the 2000 census.

Liesi E Hebert, Paul A Scherr, Julia L Bienias … (2003)

Current and future estimates of Alzheimer disease (AD) are essential for public health planning. To provide prevalence estimates of AD for the US population from 2000 through 2050. Alzheimer disease incidence estimates from a population-based, biracial, urban study, using a stratified random sampling design, were converted to prevalence estimates and applied to US Census Bureau estimates of US population growth. A geographically defined community of 3 adjacent neighborhoods in Chicago, Ill, applied to the US population. Alzheimer disease incidence was measured in 3838 persons free of AD at baseline; 835 persons were evaluated for disease incidence. Main Outcome Measure Current and future estimates of prevalence of clinically diagnosed AD in the US population. In 2000, there were 4.5 million persons with AD in the US population. By 2050, this number will increase by almost 3-fold, to 13.2 million. Owing to the rapid growth of the oldest age groups of the US population, the number who are 85 years and older will more than quadruple to 8.0 million. The number who are 75 to 84 years old will double to 4.8 million, while the number who are 65 to 74 years old will remain fairly constant at 0.3 to 0.5 million. The number of persons with AD in the US population will continue to increase unless new discoveries facilitate prevention of the disease.

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Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system--too little activation is bad, too much is even worse.

Wojciech Danysz, Albrecht Stöffler, Peter Parsons (2007)

The neurotransmitter glutamate activates several classes of metabotropic receptor and three major types of ionotropic receptor--alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA). The involvement of glutamate mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD) is finding increasing scientific acceptance. Central to this hypothesis is the assumption that glutamate receptors, in particular of the NMDA type, are overactivated in a tonic rather than a phasic manner. Such continuous, mild, chronic activation ultimately leads to neuronal damage/death. Additionally, impairment of synaptic plasticity (learning) may result not only from neuronal damage per se but may also be a direct consequence of this continuous, non-contingent NMDA receptor activation. Complete NMDA receptor blockade has also been shown to impair neuronal plasticity, thus, both hypo- and hyperactivity of the glutamatergic system leads to dysfunction. Memantine received marketing authorization from the EMEA (European Medicines Agency) for the treatment of moderate to severe AD in Europe and was subsequently also approved by the FDA (Food and Drug Administration) for use in the same indication in the USA. Memantine is a moderate affinity, uncompetitive NMDA receptor antagonist with strong voltage-dependency and fast kinetics. This review summarizes existing hypotheses on the mechanism of action (MOA) of memantine in an attempt to understand how the accepted interaction with NMDA receptors could allow memantine to provide both neuroprotection and reverse deficits in learning/memory by the same MOA.

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Alzheimer's disease, β-amyloid, glutamate, NMDA receptors and memantine--searching for the connections.

Wojciech Danysz, Chris G Parsons (2012)

β-amyloid (Aβ) is widely accepted to be one of the major pathomechanisms underlying Alzheimer's disease (AD), although there is presently lively debate regarding the relative roles of particular species/forms of this peptide. Most recent evidence indicates that soluble oligomers rather than plaques are the major cause of synaptic dysfunction and ultimately neurodegeneration. Soluble oligomeric Aβ has been shown to interact with several proteins, for example glutamatergic receptors of the NMDA type and proteins responsible for maintaining glutamate homeostasis such as uptake and release. As NMDA receptors are critically involved in neuronal plasticity including learning and memory, we felt that it would be valuable to provide an up to date review of the evidence connecting Aβ to these receptors and related neuronal plasticity. Strong support for the clinical relevance of such interactions is provided by the NMDA receptor antagonist memantine. This substance is the only NMDA receptor antagonist used clinically in the treatment of AD and therefore offers an excellent tool to facilitate translational extrapolations from in vitro studies through in vivo animal experiments to its ultimate clinical utility. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

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Author and article information

Journal

Journal ID (nlm-ta): Mater Sociomed

Journal ID (iso-abbrev): Mater Sociomed

Title: Materia Socio-Medica

Publisher: AVICENA, d.o.o., Sarajevo (Bosnia and Herzegovina )

ISSN (Print): 1512-7680

ISSN (Electronic): 1986-597X

Publication date (Print): June 2016

Publication date (Electronic): 01 June 2016

Volume: 28

Issue: 3

Pages: 235-238

Affiliations

[1 ]Department of Biochemistry, Faculty of Pharmacy, University of Tuzla, Tuzla, Bosnia and Herzegovina

[2 ]Department of Clinical Pharmacy, Faculty of Pharmacy, University of Tuzla, Tuzla, Bosnia and Herzegovina

[3 ]Berlin- Chemie Menarini, Representative Office in Sarajevo, Bosnia and Herzegovina

[4 ]Pharmacy Pharmacom, Tuzla, Bosnia and Herzegovina

[5 ]General Hospital Tesanj, Bosnia and Herzegovina

[6 ]Department of Pathophysiology, Faculty of Pharmacy, Sarajevo, Bosnia and Herzegovina

Author notes

Corresponding author: Besim Prnjavorac, General Hospital Tesanj, Department of Pathophysiology, Faculty of Pharmacy, Sarajevo, Bosnia and Herzegovina. ORCID ID: http://orcid.org/0000-0003-0331-055X). Phone: +387 61 166 850, E-mail: pbesim@ 123456bih.net.ba

Article

Publisher ID: MSM-28-235

DOI: 10.5455/msm.2016.28.235-238

PMC ID: 4949049

PubMed ID: 27482169

SO-VID: b1019bc7-4773-41f2-975f-510146d3aeb0

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 23 March 2016

Date accepted : 15 May 2016

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THE ROLE OF CYSTEINE PROTEASE IN ALZHEIMER DISEASE

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Abstract

Introduction:

Review:

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Most cited references 37

Alzheimer disease in the US population: prevalence estimates using the 2000 census.

Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system--too little activation is bad, too much is even worse.

Alzheimer's disease, β-amyloid, glutamate, NMDA receptors and memantine--searching for the connections.

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Cited by 12

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