Intravenously Injected Amyloid-Beta Peptide With Isomerized Asp7 And Phosphorylated Sera Residues Inhibits Cerebral Beta-Amyloidosis In A Beta Pp/Ps1 Transgenic Mice Model Of Alzheimer'S Disease

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