A Comparative Interaction between Copper Ions with Alzheimer's β Amyloid Peptide and Human Serum Albumin

The interaction of Cu2+ with the first 16 residues of the Alzheimer's amyliod β peptide, Aβ(1–16), and human serum albumin (HSA) were studied in vitro by isothermal titration calorimetry at pH 7.2 and 310 K in aqueous solution. The solvation parameters recovered from the extended solvation model indicate that HSA is involved in the transport of copper ion. Complexes between Aβ(1–16) and copper ions have been proposed to be an aberrant interaction in the development of Alzheimer's disease, where Cu2+ is involved in Aβ(1–16) aggregation. The indexes of stability indicate that HSA removed Cu2+ from Aβ(1–16), rapidly, decreased Cu-induced aggregation of Aβ(1–16), and reduced the toxicity of Aβ(1–16) + Cu2+ significantly.


Introduction
One of the hallmarks of Alzheimer's disease is the accumulation of amyloid plaques between nerve cells (neurons) in the brain. Beta amyloid is a protein fragment snipped from an amyloid precursor protein (APP). In a healthy brain, these protein fragments are broken down and eliminated. In Alzheimer's disease, the fragments accumulate to form hard, insoluble plaques. Alzheimer's disease and heart disease were made worse by excess copper and iron. Researchers are still trying to fully understand how its plaques and tangles lead to memory loss and other symptoms and how to reverse those changes to prevent or stop the disease. However, there are treatments available today that can help patients manage the symptoms of Alzheimer's disease and delay its progression. Acetylcholine helps pass messages between certain brain cells involved in memory. In Alzheimer's disease, these brain cells start to die and the amount of acetylcholine is reduced. Cholinesterase inhibitors reduce the breakdown of acetylcholine and increase its levels in the brain. This reduces some of the symptoms of Alzheimer's disease. HSA carries metal ions, including physiological Ca 2+ , Zn 2+ , Co 2+ , and Cu 2+ , as well as toxic Cd 2+ and Ni 2+ [1][2][3][4][5].
Although the etiology of cognitive impairment in Alzheimer's disease (AD) is not fully understood, it has been reported that acetylcholine-producing neurons degenerate in the brains of patients with Alzheimer's disease. The degree of this cholinergic loss has been correlated with degree of cognitive impairment and density of amyloid plaque.
Galantamine, a tertiary alkaloid, is a competitive and reversible inhibitor of acetylcholinesterase. It is possible to postulate galantamine's action therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. If this mechanism is correct, galantamine's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. In humans, Cu 2+ is necessary for the development of connective tissue, nerve coverings, and bone. Cu 2+ also participates in both Fe and energy metabolism. Cu 2+ acts as a reductant in the enzymes, superoxide dismutase, cytochrome oxidase, lysyl oxidase, dopamine hydroxylase, and several other oxidases that reduce molecular oxygen. Cu 2+ deficiency in humans is rare, but when it occurs it leads to normocytic, hypochromic anemia, leucopenia and neuropenia, and inclusive osteoporosis in children. Excessive dietary Zn 2+ can cause Cu 2+ deficiency. Chronic Cu 2+ toxicity is rare in humans, and mostly associated with liver damage. Curcumin has been implicated in resolving and preventing Alzheimer's disease-associated plaques or deposits both in vivo and vitro. Epidemiological data suggest that the consumption of curcumin is linked to a lower incidence of Alzheimer's disease. However, the solubility of curcumin in aqueous solutions is exceedingly low, which limits its systemic absorption and therapeutic potential. A new method is proposed to treat or prevent amyloid plaque formation associated with Alzheimer's disease by injection of highly concentrated blood serum-solubilized curcumin [2,[6][7][8][9][10]. The objective of this study was to assess the conformational changes of HSA and Aβ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) due to their Aβ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) binding to Cu 2+ ion.

Materials and Method
Human serum albumin (HSA; MW = 66411 gr/mol) and tris salt are obtained from Sigma Chemical Co. The isothermal titration microcalorimetric experiments were performed with the four-channel commercial microcalorimetric system. Copper solution (4 mM) was injected by use of a Hamilton syringe into the calorimetric titration vessel, which contained 1.8 mL HSA (27.43 μM). Injection of copper solution into the perfusion vessel was repeated 28 times, with 10 μL per injection. The calorimetric signal was measured by a digital voltmeter that was part of a computerized recording system. The heat of each injection was calculated by the "Thermometric Digitam 3" software program. The heat of dilution of the copper solution was measured as described above except HSA was excluded. The heats of HSA + Cu 2+ interactions have been calculated in kJmol −1 and shown graphically in Figure 1.
Hopefully this suggestion proves successful, a human application would be of novel benefit for either preventing Alzheimer's disease plaque formation or possibly reverse existing plaques.

Conclusion
The large and positive δ θ A and δ θ B values indicate that Cu 2+ stabilizes the HSA structure significantly. The negative δ θ A and δ θ B values indicate that complexes between Aβ(1-16) and copper ions have been proposed to be an aberrant interaction implicated in the development of Alzheimer's disease, where Cu 2+ is involved in Aβ(1-16) aggregation. The precious approach is that it is possible to predict a roughly treatment using the extended solvation model in vitro.