Proteomic Profiling Reveals Mitochondrial Dysregulation in Rapidly Progressive Alzheimer’s: Role of DLDH in Amyloid Beta Aggregation

TL;DR

This study finds that mitochondrial dysfunction, particularly involving the protein DLDH, is linked to rapid progression in Alzheimer’s disease.

Contribution

The study identifies DLDH as a novel player in amyloid beta aggregation and rapid Alzheimer’s progression.

Findings

79 proteins were differentially regulated in rapidly progressive Alzheimer’s compared to controls and sporadic cases.

Mitochondrial dysfunction and glucose metabolism issues were prominent in rapidly progressive Alzheimer’s.

DLDH levels and localization were altered in rapidly progressive Alzheimer’s and may influence amyloid beta aggregation.

Abstract

Alzheimer’s disease (AD) is presented as multiple clinical variants depending upon the rate of progression and familial background; however, the exact molecular mechanisms associated with these subtypes and their treatments are yet to be understood. The current study is based on a global proteome analysis of brain samples from patients (n = 38) with rapidly progressive AD (rpAD—survival time < 3 years), sporadic AD (spAD—survival time of 8–10 years), and healthy controls. Proteome analysis revealed a differential regulation of 79 proteins and highlighted the dysregulation of mitochondrial machinery and glucose metabolism in rpAD. Dihydrolipoamide dehydrogenase (DLDH), a mitochondrial oxidoreductase, showed a significant reduction and delocalization in rpAD. In vitro analysis revealed a potential role of DLDH in the aggregation of amyloid beta. Rapid progression in AD may be influenced by the energy homeostasis and redox dysfunction linked with the DLDH.

The online version contains supplementary material available at 10.1007/s12035-025-05327-0.

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