E22G Pathogenic Mutation of β-Amyloid (Aβ) Enhances Misfolding of Aβ40 by Unexpected Prion-like Cross Talk between Aβ42 and Aβ40

Abstract

Cross-seeding of misfolded amyloid proteins is postulated to induce cross-species infection of prion diseases. In sporadic Alzheimer's disease (AD), misfolding of 42-residue β-amyloid (Aβ) is widely considered to trigger amyloid plaque deposition. Despite increasing evidence that misfolded Aβ mimics prions, interactions of misfolded 42-residue Aβ42 with more abundant 40-residue Aβ40 in AD are elusive. This study presents in vitro evidence that a heterozygous E22G pathogenic ("Arctic") mutation of Aβ40 can enhance misfolding of Aβ via cross-seeding from wild-type (WT) Aβ42 fibril. Thioflavin T (ThT) fluorescence analysis suggested that misfolding of E22G Aβ40 was enhanced by adding 5% (w/w) WT Aβ42 fibril as "seed", whereas WT Aβ40 was unaffected by Aβ42 fibril seed. C SSNMR analysis revealed that such cross-seeding prompted formation of E22G Aβ40 fibril that structurally mimics the seed Aβ42 fibril, suggesting unexpected cross talk of Aβ isoforms that potentially promotes early onset of AD. The SSNMR approach is likely applicable to elucidate structural details of heterogeneous amyloid fibrils produced in cross-seeding for amyloids linked to neurodegenerative diseases.

Cationic polymethacrylate-copolymer acts as an agonist for β-amyloid and antagonist for amylin fibrillation

“…Structural changes in Aβ by affecting these central residues by mutation (E22G), disruption of the D23-K28 salt-bridge or binding of hexapeptide of genetic Aβ variants has been reported previously to be crucial in promoting Aβ40 aggregation and induction of terminal β-structure. [35][36][37][38] In conclusion, we have demonstrated the counter activities of a cationic PMAQA polymer on two different amyloidogenic peptides that are connected to AD and T2D. At sub-micromolar concentration, PMAQA showed significant inhibitory activity in hIAPP aggregation; whereas it significantly accelerated A40's aggregation by quickly altering the equilibrium state of A40 from an unfolded structure to a β-sheet structure.…”

Medical Plants and Nutraceuticals for Amyloid-β Fibrillation Inhibition

“…For this work, we have selected eight of them for the investigation of in vitro inhibition tests to prevent oligomerization/fibrillation of amyloid-β 1–40 (Aβ 40 ) and Methionine amyloid-β 1–40 (MAβ 40 ). Both peptides are of major relevance in Alzheimer’s disease research and considered toxic directly or via transformation to Aβ 42 [11] destroying nerve cells: destructing relevant molecule- and affecting ion-transport. This decline in interaction abilities of nerve cells is well-known, leading to loss of memory and physical control of critical body functions.…”

Multistep changes in amyloid structure that are induced by cross-seeding on a rugged energy landscape

“…cross-talk between Aβ42 and Aβ40 (22). When this model is adapted to the energy landscape observed in this study, the thermodynamically permissible structures per protein correspond reasonably to a number of energy minima distributing over the landscape.…”

“…The cross-seeding has been reported not only between isoforms of the same protein but also between different proteins, and it is considered to be important for understanding pathology and furthermore, cross-talk between different amyloid diseases (50)(51)(52). Given that heterologous proteins are actually involved in the pathology of several diseases, such as Alzheimer's disease, prion disease, Parkinson's disease and type 2 diabetes (22,24), accelerating researches on crossseeding will pave new perspectives on the mechanism of pathology at the level of protein molecules.…”