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Aging-Induced Memory Loss

#A-1780


The Primary Role of Brain Tissue Hydration in Aging-Induced Memory Loss in Rats

Tech Area / Field

  • BIO-CHM/Biochemistry/Biotechnology
  • MED-DIS/Disease Surveillance/Medicine

Status
3 Approved without Funding

Registration date
14.09.2009

Leading Institute
Life Sciences International Postgraduate Educational Center, Armenia, Yerevan

Collaborators

  • University of Iowa / Department of Anatomy and Cell Biology, USA, IA, Iowa City

Project summary

Although the fact that aging-induced memory loss is accompanied by body tissue dehydration, the functional role of neuronal dehydration in the generation of nerve disorders is not paid adequate attention by researchers. At present the oxidative stress and extracellular deposits (senile plaques) of amyloid-β (Aβ) peptide generation are considered to be a key pathogenic mechanism in aging-induced sclerosis and in the increase of nerve disorder generation risk. However, the nature of metabolic mechanisms between neuronal hydration and oxidative stress-induced generation of Aβ is not clear yet. Our early studies have shown that membrane proteins, having enzymatic, receptor and channel-forming properties, are functionally active and inactive (reserve), the ratio of which is changed depending on cell hydration (membrane packing). Na+/K+ pump, being the main regulator of cell volume, also modulates a number of mechanisms involved in the regulation of cell volume like as Na+/Ca2+ and Na+/H+ exchange activities and cytoskeleton phosphorylation processes. It was also shown that Na+/K+ pump-induced cell volume regulation serves as a powerful mechanism through which the autoregulation of pump and regulation of membrane function is realized. As the dysfunction of Na+/K+ pump is a common consequence of aging and nerve disorders, it predicts the accumulation of intracellular Ca ions. The latter, being a strong inhibitor for Na+/K+-ATPase, switches on the following pathway: ATP accumulation; stimulation of intracellular cAMP formation; the increase of cytoskeleton phosphorylation. While the contraction of Ca ions brings to cell dehydration. The fact that there is a close correlation between electrogenic Na+/K+ pump and electrogenic Na+/Ca2+ exchange realized through the intracellular cAMP/cGMP, which plays a crucial role in the regulation of intracellular Ca homeostasis, allow us to conclude that Ca efflux system has an essential role in the protection of Na+/K+ pump activity from the pathogenic factor-induced increase of intracellular Ca ions. Previously it was shown that intracellular cGMP plays a key role in the activation of Ca efflux through Na+/Ca2+ exchange and Ca pump mechanisms. As the cytoplasmic guanylyl cyclase activity, like other proteins, depends on its hydration, it is suggested that the aging-induced inactivation of cGMP formation could serve as a primary mechanism for switching on the pathogenic pathways (Na+/K+ pump weakness, intracellular Ca ions and cAMP accumulation, oxidative stress, Aβ generation, DNA demethylation, etc). Therefore, it is suggested that for understanding the nature of the mechanism underlay in the ground of aging-induced memory loss and the increase of nerve disorders risk, it is extremely important to study the multisided role of osmotic stress on intracellular enzymes activity responsible for intracellular Ca homeostasis. This knowledge will greatly impact on the strategies designed to decrease the aging–induced risk of neuronal dysfunction. The overall aim of present project is first of all to proof this statement. For this purpose the comparative study of learning and memory of 3- and 48-week-old rats at different osmotic stress conditions, as well as brain cortex cell hydration, electrogenic Na+/K+ pump and Na+/Ca2+ exchange activities, intracellular signaling system (cAMP and cGMP contents), the number of functionally active 3H-ouabain receptors (Na+/K+ pump units), Ca-dependent potassium channel properties in membrane, DNA methylation and A formation of brain zones will be performed. For the study of learning and memory process of 3- and 48-week-old rats computerized T-maze method will be used. The following modern physiological, biophysical and biochemical methods would be used for the study of the present project:
  1. Isotope method for studying ions membrane transport and counting the number of pump units (3H-ouabain receptors) in membrane and DNA methylation.
  2. Immunoassay method for the measurement of the content of intracellular cyclic nucleotides.
  3. Light microscopic and impedance-metric methods for studying structured properties and neurons hydration properties.
  4. Luminescent method for the determination of H2O2 and NO contents in extracellular medium.
  5. Standard Voltage-clamp and Patch –clamp methods for the characterization of ionic channel properties.
  6. Standard biochemical method for the detection of A peptides in brain tissue.


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