Intravenously Injected Amyloid-ß Peptide With Isomerized Asp7 and Phosphorylated Ser8 Residues Inhibits Cerebral ß-Amyloidosis in AßPP/PS1 Transgenic Mice Model of Alzheimer's Disease.

ABSTRACT

Cerebral ß-amyloidosis, an accumulation in the patient's brain of aggregated amyloid-ß (Aß) peptides abnormally saturated by divalent biometal ions, is one of the hallmarks of Alzheimer's disease (AD). Earlier, we found that exogenously administrated synthetic Aß with isomerized Asp7 (isoD7-Aß) induces Aß fibrillar aggregation in the transgenic mice model of AD. IsoD7-Aß molecules have been implied to act as seeds enforcing endogenous Aß 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 Aß species, we hypothesize that upon phosphorylation of Ser8, isoD7-Aß loses its ability to form zinc-bound oligomeric seeds. In this work, we found that (i) in vitro isoD7-Aß with phosphorylated Ser8 (isoD7-pS8-Aß) is less prone to spontaneous and zinc-induced aggregation in comparison with isoD7-Aß and intact Aß as shown by thioflavin T fluorimetry and dynamic light scattering data, and (ii) intravenous injections of isoD7-pS8-Aß significantly slow down the progression of institutional ß-amyloidosis in AßPP/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 Aß species in the modulation of cerebral ß-amyloidosis and demonstrate that isoD7-pS8-Aß can serve as a potential molecular tool to block the aggregation of endogenous Aß in AD.