Clinically relevant stereochemistry reprograms amyloid proteome for aggregation cross-talk–conferred neuroprotection

The stereochemical diversity of Aβ42 in the brains of patients with Alzheimer’s disease (AD) is a clinically recognized but poorly understood phenomenon. A critical gap in our knowledge is how the complex mixture of these stereoisomers collectively influences the aggregation pathway and neurotoxicity of Aβ42 at the molecular level. Drawing from stereoproteome data from AD patient brain tissues and previous studies, we engineered a panel of stereoisomers to more simply simulate the stereochemical diversity of the AD marker Aβ42. We found that the coexistence of L-Aβ42 with specific D-isomers initiates a potent antagonistic effect, suppressing the formation of toxic fibrils. This stereochemically driven antagonism conferred notable neuroprotection, suggesting an endogenous protective mechanism. This proof-of-concept work elucidates at the molecular level that by regulating the stereochemical composition of Aβ, its inherent cellular protective antagonistic effect can be activated, providing unprecedented molecular basis for understanding the disease mechanism and subsequent possible clinical research.