Phosphorylation at Ser8 as an Intrinsic Regulatory Switch to Regulate the Morphologies and Structures of Alzheimer's 40-residue ß-Amyloid (Aß40) Fibrils.

ABSTRACT

Polymorphism of amyloid-ß (Aß) fibrils, implying different fibril structures, may play important pathological roles in Alzheimer's disease (AD). Morphologies of Aß fibrils were found to be sensitive to fibrillation conditions. Herein, the Ser8-phosphorylated Aß (pAß), which is assumed to specially associate with symptomatic AD, is reported to modify the morphology, biophysical properties, cellular toxicity, and structures of Aß fibrils. Under the same fibrillation conditions, pAß favors the formation of fibrils (Fpß), which are different from the wild-type Aß fibrils (Fß). Both Fß and Fpß fibrils show single predominant morphologies. Compared with Fß, Fpß exhibits higher propagation efficiency and higher neuronal cell toxicity. The residue-specific structural differences between the Fß- and Fpß-seeded Aß fibrils were identified using magic angle spin NMR. Our results suggest a potential regulatory mechanism of phosphorylation on Aß fibril formation in AD and imply that the post-translationally modified Aß, especially the phosphorylated Aß, may be an important target for the diagnosis or treatment of AD at specific stages.