Front Neurosci, 2018, 12(AUG):518

Intravenously injected amyloid-β peptide with isomerized Asp7 and phosphorylated Ser8 residues inhibits cerebral β-amyloidosis in AβPP/PS1 transgenic mice model of Alzheimer's disease

Cerebral β-amyloidosis, an accumulation in the patient's brain of aggregated amyloid-β (Aβ) peptides abnormally saturated by divalent biometal ions, is one of the hallmarks of Alzheimer's disease (AD). Earlier, we found that exogenously administrated synthetic Aβ with isomerized Asp7 (isoD7-Aβ) induces Aβ fibrillar aggregation in the transgenic mice model of AD. IsoD7-Aβ molecules have been implied to act as seeds enforcing endogenous Aβ to undergo pathological aggregation through zinc-mediated interactions. On the basis of our findings on zinc-induced oligomerization of the metal-binding domain of various Aβ species, we hypothesize that upon phosphorylation of Ser8, isoD7-Aβ loses its ability to form zinc-bound oligomeric seeds. In this work, we found that (i) in vitro isoD7-Aβ with phosphorylated Ser8 (isoD7-pS8-Aβ) is less prone to spontaneous and zinc-induced aggregation in comparison with isoD7-Aβ and intact Aβ as shown by thioflavin T fluorimetry and dynamic light scattering data, and (ii) intravenous injections of isoD7-pS8-Aβ significantly slow down the progression of institutional β-amyloidosis in AβPP/PS1 transgenic mice as shown by the reduction of the congophilic amyloid plaques' number in the hippocampus. The results support the role of the zinc-mediated oligomerization of Aβ species in the modulation of cerebral β-amyloidosis and demonstrate that isoD7-pS8-Aβ can serve as a potential molecular tool to block the aggregation of endogenous Aβ in AD.

Kozin SA, Barykin EP, Telegin GB, Chernov AS, Adzhubei AA, Radko SP, Mitkevich VA, Makarov AA

IBCH: 6624
Ссылка на статью в журнале: https://www.frontiersin.org/article/10.3389/fnins.2018.00518/full
Кол-во цитирований на 08.2020: 3
Данные статьи проверены модераторами 2018-08-23