Philippe Tsvetkov et al. present new perspective on Alzheimer's disease drug development

A team of researchers (Philippe Tsvetkov et al.) from Engelhardt Institute of Molecular Biology (Moscow, Russia) have shed light on molecular mechanisms of Alzheimer's disease with perspective on development of novel drug therapies. The study, published in Biophysical Journal, provides insights into molecular mechanisms of Zinc-induced aggregation of amyloid-β peptide.

Zinc-induced aggregation of amyloid-β peptide (Aβ) is a hallmark molecular feature of Alzheimer's disease. The team headed by Philippe Tsvetkov provided direct thermodynamic evidence that elucidates the role of the Aβ region 6–14 as the minimal Zn2+ binding site wherein the ion is coordinated by His6, Glu11, His13, and His14. With the help of isothermal titration calorimetry and quantum mechanics/molecular mechanics simulations, the region 11–14 was determined as the primary zinc recognition site and considered an important drug-target candidate to prevent Zn2+-induced aggregation of Aβ.

Alzheimer's disease, a fatal neurodegenerative disorder of the elderly, is characterized by extracellular depositions of amyloid-β peptide (Aβ) saturated with metal ions. It is believed that Zn2+ ions play a key role in pathological aggregation of Aβ and therefore affect the pathogenesis of Alzheimer's disease. The insights into molecular mechanism of Zinc-induced aggregation allow to consider Aβ(11–14) tetrapeptide as a primary Zn2+-recognition site of Aβ and an important drug target candidate to prevent Zn2+-induced aggregation of Aβ.

Minimal Zn2+ Binding Site of Amyloid-β
Philipp O. Tsvetkov, Alexandra A. Kulikova, Andrey V. Golovin, Yaroslav V. Tkachev, Alexander I. Archakov, Sergey A. Kozin, and Alexander A. Makarov
Biophysical Journal, Volume 99, Issue 10, L84-L86, 17 November 2010