Zn-dependent β-amyloid aggregation and its reversal by the tetrapeptide HAEE

Mitkevich, V.A.; Barykin, E.P.; Eremina, S.; Pani, B.; Katkova-Zhukotskaya, O.; Polshakov, V.I.; Adzhubei, A.A.; Kozin, S.A.; Mironov, A.S.; Makarov, A.A.; Nudler, E.

Авторы: Mitkevich V.A., Barykin E.P., Eremina S., Pani B., Katkova-Zhukotskaya O., Polshakov V.I., Adzhubei A.A., Kozin S.A., Mironov A.S., Makarov A.A., Nudler E.
Журнал: Aging and disease
Том: 13
Год издания: 2022
Издательство: JKL International
Местоположение издательства: California, United States
Первая страница: 1
Последняя страница: 10
Номер статьи: in press
DOI: 10.14336/AD.2022.0827
Аннотация: The pathogenesis of Alzheimer's disease (AD) is associated with the formation of cerebral amyloid plaques, the main components of which are the modified Aβ molecules as well as the metal ions. Aβ isomerized at Asp7 residue (isoD7-Aβ) is the most abundant isoform in amyloid plaques. We hypothesized that the pathogenic effect of isoD7-Aβ is due to the formation of zinc-dependent oligomers, and that this interaction can be disrupted by the rationally designed tetrapeptide (HAEE). Here, we utilized surface plasmon resonance, nuclear magnetic resonance, and molecular dynamics simulation to demonstrate Zn2+-dependent oligomerization of isoD7-Aβ and the formation of a stable isoD7-Aβ:Zn2+:HAEE complex incapable of forming oligomers. To demonstrate the physiological importance of zinc-dependent isoD7-Aβ oligomerization and the ability of HAEE to interfere with this process at the organismal level, we employed transgenic nematodes overexpressing human Aβ. We show that the presence of isoD7-Aβ in the medium triggers extensive amyloidosis that occurs in a Zn2+-dependent manner, enhances paralysis, and shortens the animals’ lifespan. Exogenous HAEE completely reverses these pathological effects of isoD7-Aβ. We conclude that the synergistic action of isoD7-Aβ and Zn2+ promotes Aβ aggregation and that the selected small molecules capable of interrupting this process, such as HAEE, can potentially serve as anti-amyloid therapeutics.
Добавил в систему: Польшаков Владимир Иванович

	ИСТИНА	Войти в систему Регистрация
	ИПМех РАН
	Главная Поиск Статистика О проекте Помощь

ИСТИНА

ИПМех РАН

Zn-dependent β-amyloid aggregation and its reversal by the tetrapeptide HAEEстатья

Прикрепленные файлы