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Apoaequorin

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Apoaequorin, [apo-eck-wàrin] Also known as Aequorin it, is a photoprotein isolated from luminescent jellyfish (like various Aequorea species, e.g., Aequorea victoria) and a variety of other marine organisms.[1] It was originally isolated from the coelenterate by Dr. Osamu Shimomura. Using a means of following the luminescence as a marker, they were able to track calcium's role in various physiological processes, which lead to a 2008 Nobel prize in chemistry for Drs. Shimomura, Marti Chalfie and Roger Y. Tsien.[2]

Aequorin ribbon diagram from Protein Data Bank database with prosthetic group coelenterazine in blue

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Structure

Aequorin is composed of two distinct units, the apoprotein apoaequorin, with an approximate molecular weight of 22 Atomic mass unit, and the prosthetic group coelenterazine, a luciferin.

Company History

Mark Underwood was an undergraduate, pre-med student studying neurophysiology, when he came upon articles about people in Australia who were victims of jelly-fish stings. He started asking questions like: What was the mechanism? Why did the sting symptoms cause a syndrome similar to multiple sclerosis? and Why were the jelly-fish immune to their own stings? His research lead, together with Mike Beaman, to the founding of Qunicy Bioscience in 2004, where he currently serves as President. It was this company that developed the process for synthesizing the apoaequorin. Apoaequorin is no longer extracted from the jellyfish, [3] rather rapidly dividing host cells are “taught” to grow the unique protein. The end result is the exact composition of apoaequorin without any of the heavy metal pollution to which jellyfish may be exposed in the ocean. As they currently own all the patents on apoaequorin, they are the sole source of this substance, which is sold under the name of "Prevagen".

The company’s products, according to their website, focus on "alleviating the consequences of impaired calcium homeostasis – the imbalance of calcium ions commonly thought to be related to neurodegenerative diseases such as Alzheimer’s and dementia, as well as normal age-related memory loss".

Mechanism

After the age of 40, [4] there is a diminishing supply of calcium-binding proteins in neurons which help protect against prolonged accumulations of intracellular calcium. Unlike calcium in the bones or teeth which help provided strength and structure, ionic calcium in the nervous system is required for the electrical signals of the nervous system to travel to, from and within the brain.

The depletion of calcium-binding proteins in aging creates a scenario in which neurons are vulnerable to excitotoxicity [4]brought on by excess calcium and can lead to cell death. This mechanism has been identified as a key mechanism in age-related cognitive decline.

The molecule is a proven suitable replacement for human endogenous calcium-binding proteins.[5]

The two components of apoaequorin a/k/a aequorin reconstitute spontaneously, forming the functional protein.[citation needed] The protein bears three EF hand motifs that function as binding sites for Ca2+ ions. When Ca2+ occupies such sites, the protein undergoes a conformational change and converts through redox its prosthetic group, coelenterazine, into excited coelenteramide and carbon dioxide. As the excited coelenteramide relaxes to the ground state, blue light (wavelength = 469 nm) is emitted.

Uses in Biology and Medicine

Since the emitted light can be easily detected with a luminometer, aequorin has become a useful tool in molecular biology for the measurement of intracellular Ca2+ levels. Cultured cells expressing the aequorin gene can effectively synthesize aequorin: However, Recombinant DNA expression yields only the apoprotein, therefore it is necessary to add coelenterazine into the culture medium of the cells to obtain a functional protein and thus use its blue light emission to measure Ca2+ concentration. Coelenterazine is a hydrophobic molecule, and therefore is easily taken up across plant and fungal cell walls, as well as the plasma membrane of higher eukaryotes, making aequorin suitable as a (calcium in biology) in plants, fungi, and mammalian cells.[6][7]

Aequorin has a number of advantages over other Ca2+ indicators: It has a low leakage rate from cells, lacks phenomena of intracellular compartmentalization or sequestration, and does not disrupt cell functions or embryo development. Moreover the light emitted by the oxidation of coelenterazine does not depend on any optical excitation, so problems with auto-fluorescence are eliminated.[8] The primary limitation of aequorin is that the prosthetic group coelenterazine is irreversibly consumed to produce light, and requires continuous addition of coelenterazine into the media. Such issues led to developments of other genetically encoded calcium sensors including the calmodulin-based sensor cameleon (protein)[9] developed by Roger Tsien and the troponin-based sensor, TN-XXL, developed by Oliver Griesbeck.[10]

Commercial quantities available for oral supplementation in humans are available under the name Prevagen.[11]

Dosage availability

"Prevagen" is available as:

  • Regular strength, @ 10mg/capsule
  • Extra strength, @ 20mg/capsule, and
  • Professional strength @ 40mg/capsule

Research

In pre-clinical studies conducted at the University of Wisconsin-Milwaukee, apoaequorin has proven neuroprotective. In a double-blind, placebo-controlled study utilizing computer assessments over 90 days, Prevagen improved executive function and short-term memory scores by 29% compared to placebo in 100 participants who had memory concerns.[5]

  • 2011 - Underwood,M. et al reported in a placebo controlled double blind study involving 222 patients, published in "Alzheimer's & Dementia: The Journal of the Alzheimer's Association" that, over a three month study period, participants were tested five times with standard measures of cognitive performance, and the apoaequorin group showed improvements in verbal and visual learning, memory and delayed recall that were not seen in the placebo group. Overall, they wrote that "Results suggest an important role and potential therapeutic utility for apoaequorin in delaying or modifying the decline in cognitive functioning associated with aging." [12]
  • 2011 - In another study published in the same journal, Underwood together with lead researcher, Norton Milgram described testing the effects of Apoaequorin vs Anipryl in a group of aging beagle dogs, and measuring for cognitive functions. The outcomes reported were significant improved in the group receiving Apoequoin vs those receiving the Anipryl. [13]

References

  1. Shimomura O (1995). "A short story of aequorin.". Biol Bull. (Biological Bulletin, Vol. 189, No. 1) 189 (1): 1–5. doi:10.2307/1542194. PMID 7654844. 
  2. Shimomura O, Johnson FH, Saiga Y (1962). "Extraction, purification and properties of aequorin, a bioluminescent protein from the luminous hydromedusan, Aequorea". J Cell Comp Physiol 59 (3): 223–239. doi:10.1002/jcp.1030590302. PMID 13911999. 
  3. Staff writer. "Quality Production". Quincy bioscience. http://quincybioscience.com/technology/. 
  4. 4.0 4.1 Staff writer. "Calcium in the nervous system". Quincy bioscience. http://prevagenpro.com/practitioners/about/. 
  5. 5.0 5.1 Staff writer. "Prevagen professional". Quincy bioscience. http://prevagenpro.com/practitioners/about/. 
  6. Blinks JR, Wier WG, Hess P, Prendergast FG (1982). "Measurement of Ca2+ concentrations in living cells". Prog Biophys Mol Biol 40 (1–2): 1–114. doi:10.1016/0079-6107(82)90011-6. PMID 6758036. 
  7. Montero M, Brini M, Marsault R, Alvarez J, Sitia R, Pozzan T, Rizzuto R (1995). "Monitoring dynamic changes in free Ca2+ concentration in the endoplasmic reticulum of intact cells". EMBO J 14 (22): 5467–75. PMID 8521803. 
  8. Kendall JM, Badminton MN, Sala-Newby GB, Campbell AK, Rembold CM (1996). "Recombinant apoaequorin acting as a pseudo-luciferase reports micromolar changes in the endoplasmic reticulum free Ca2+ of intact cells". Biochem J 318: 383–7. PMID 8809023. 
  9. Miyawaki A, Llopis J, Heim R, McCaffery JM, Adams JA, Ikurak M, Tsien RY (1997). "Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin". Nature 388 (6645): 882–7. doi:10.1038/42264. PMID 9278050. 
  10. Heim N, Griesbeck O (2004). "Genetically encoded indicators of cellular calcium dynamics based on troponin C and green fluorescent protein". J Biol Chem 279 (14): 14280–6. doi:10.1074/jbc.M312751200. PMID 14742421. http://www.jbc.org/cgi/content/abstract/279/14/14280. 
  11. http://www.prevagen.com/science/
  12. Underwood, M; Sivesind, P; Gabourie, T (7/2011). "Effect of apoaequorin on cognitive function". Alzheimer's & Dementia: The Journal of the Alzheimer's Association (Elsevier Inc.) 7 (4): e65. doi:10.1016/j.jalz.2011.09.138. http://www.alzheimersanddementia.com/article/S1552-5260%2811%2902857-3/fulltext. 
  13. Milgram, Norton; Underwood, M. (7/2011). "A novel mechanism for cognitive enhancement In aged dogs with the use of a calcium binding protein". Alzheimer's & Dementia: The Journal of the Alzheimer's Association (Elsevier Inc.) 7 (4): e10-11. doi:10.1016/j.jalz.2011.09.028. http://www.alzheimersanddementia.com/article/S1552-5260%2811%2902747-6/fulltext. 

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