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

Area of Science:

• Neuroscience
• Biochemistry
• Alzheimer's Disease Research

Background:

• Stereochemical diversity of amyloid-beta 42 (Aβ42) in Alzheimer's disease (AD) brains is recognized but poorly understood.
• The influence of Aβ42 stereoisomer mixtures on aggregation and neurotoxicity remains a critical knowledge gap.

Purpose of the Study:

• To investigate the molecular mechanisms by which Aβ42 stereoisomers influence aggregation and neurotoxicity.
• To simulate the stereochemical diversity of Aβ42 using engineered stereoisomers based on patient data.

Main Methods:

• Engineered a panel of Aβ42 stereoisomers to mimic AD patient brain stereoproteome.
• Assessed the aggregation pathway and neurotoxicity of mixed stereoisomer panels.

Main Results:

• The coexistence of L-Aβ42 with specific D-isomers demonstrated a potent antagonistic effect.
• This antagonism suppressed the formation of toxic Aβ42 fibrils and conferred significant neuroprotection.
• Suggests an endogenous protective mechanism mediated by Aβ stereochemistry.

Conclusions:

• Regulating the stereochemical composition of Aβ can activate inherent cellular protective antagonistic effects.
• Provides a molecular basis for understanding AD pathogenesis and potential therapeutic strategies.