Phosphorylation at Ser as an Intrinsic Regulatory Switch to Regulate the Morphologies and Structures of Alzheimer's 40-residue β-Amyloid (Aβ40) Fibrils.

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