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

• Published in: Frontiers in neuroscience Vol. 12; p. 518
• Main Authors: Kozin, Sergey A, Barykin, Evgeny P, Telegin, Georgy B, Chernov, Alexander S, Adzhubei, Alexei A, Radko, Sergey P, Mitkevich, Vladimir A, Makarov, Alexander A
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 23.08.2018; Frontiers Media S.A
• Subjects: Aging; Alzheimer's disease; amyloid-β peptide; Amyloidosis; Binding sites; Breeding of animals; Hypotheses; Intravenous administration; isoaspartate; Laboratory animals; Light scattering; Metal ions; Neuroscience; Oligomerization; Peptides; Phosphorylation; Presenilin 1; Proteins; Seeds; Senile plaques; serine phosphorylation; Transgenic animals; Transgenic mice; Zinc; β-Amyloid; United States > US; Russia; Alzheimer’s disease; transgenic mice; amyloid-β peptide; isoaspartate; cerebral amyloidosis; zinc; serine phosphorylation
• ISSN: 1662-4548; 1662-453X; 1662-453X
• DOI: 10.3389/fnins.2018.00518

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) 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.