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Clinically Relevant Aβ42 Stereochemistry-Driven Proteome Perturbation, Aggregation Crosstalk and Cytotoxicity Inhibition: ABPP

ABSTRACT: The stereochemical modification of Aβ42 discovered in the clinical samples of Alzheimer's disease (AD) patients has attracted increasing attention. However, most existing studies have focused on the characteristic analysis of a single isomer, ignoring the complex interactions of the coexistence of multiple stereochemical isomers in the physiological environment, in particular, the crosstalk effects between D-Asp and/or D-Ser modifications and natural L-type Aβ42. This study found through systematic analysis that the coexistence of L-type and stereoisomerized Aβ42 monomers showed antagonistic effects that mutually inhibited fibril formation and promoted the generation of unstable fibrils through the seed effect. This crosstalk effect shows obvious neuroprotective effects at the cellular level, and its molecular mechanism involves the adaptive regulation of ribosome function and mitochondrial pathways. This study reveals for the first time the crosstalk effect of stereoisomerized Aβ42, breaking through the limitations of traditional single isomer research. This discovery provides a new perspective for understanding the pathogenesis of AD and developing new treatment strategies based on stereochemical regulation.

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ORGANISM(S): Rattus Norvegicus (rat)

SUBMITTER: Gongyu Li

LAB HEAD: Gongyu Li

PROVIDER: PXD065394 | Pride | 2026-02-20

REPOSITORIES: Pride

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			Action	DRS
	20241210_1_L1_High_01.raw	Raw
	20241210_1_L1_High_02.raw	Raw
	20241210_1_L1_High_03.raw	Raw
	20241210_2_L1_Low_01.raw	Raw
	20241210_2_L1_Low_02.raw	Raw

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Clinically Relevant Aβ42 Stereochemistry-Driven Proteome Perturbation, Aggregation Crosstalk and Cytotoxicity Inhibition: Cytotoxicity

Project description:The stereochemical modification of Aβ42 discovered in the clinical samples of Alzheimer's disease (AD) patients has attracted increasing attention. However, most existing studies have focused on the characteristic analysis of a single isomer, ignoring the complex interactions of the coexistence of multiple stereochemical isomers in the physiological environment, in particular, the crosstalk effects between D-Asp and/or D-Ser modifications and natural L-type Aβ42. This study found through systematic analysis that the coexistence of L-type and stereoisomerized Aβ42 monomers showed antagonistic effects that mutually inhibited fibril formation and promoted the generation of unstable fibrils through the seed effect. This crosstalk effect shows obvious neuroprotective effects at the cellular level, and its molecular mechanism involves the adaptive regulation of ribosome function and mitochondrial pathways. This study reveals for the first time the crosstalk effect of stereoisomerized Aβ42, breaking through the limitations of traditional single isomer research. This discovery provides a new perspective for understanding the pathogenesis of AD and developing new treatment strategies based on stereochemical regulation.

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