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Dexter Energy Transfer Photocatalysis Enables Covalent Label-ing and Profiling of Amyloid Plagues in Alzheimer’s Disease Tissue

ABSTRACT: Amyloid plaque is a pathological hallmark in Alzheimer's disease (AD) brain with their composition associated with dis-ease etiology. Here, we report a photocatalyst, namely AmyCAT, that selectively binds to amyloid fibrils in AD brain tis-sue and undergoes Dexter energy transfer (DET) to catalyze carbene production for amyloid proximity labeling. First, we design the AmyCAT photocatalyst to generally bind different types of amyloids. Second, we energetically match the DET effect in a 12 × 4 photocatalysts-substrates array to activate diazo substrate into reactive carbene by visible green light (530~545 nm). Further, we demonstrate that the optimal AmyCAT probe catalyzes pan-amyloid protein labeling with 30-fold selectivity over folded counterparts. Mechanistic studies confirm the photocatalytic labeling is indeed via DET pro-cess, which tailors the proximity effect for spatially confined amyloid labeling. Finally, we employ the AmyCAT photo-catalyst to label, enrich and profile amyloid plagues in AD brain tissue, revealing key proteins and pathways associated with AD pathological deposition and etiology.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Rui Sun

LAB HEAD: Yu Liu

PROVIDER: PXD060111 | Pride | 2025-01-23

REPOSITORIES: pride

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	XB09117DA_C1.raw	Raw
	XB09117DA_C2.raw	Raw
	XB09117DA_C3.raw	Raw
	XB09117DA_E1.raw	Raw

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Dexter Energy Transfer Photocatalysis Enables Covalent Label-ing and Profiling of Amyloid Plagues in Alzheimer’s Disease Tissue

Project description:Amyloid plaque is a pathological hallmark in Alzheimer's disease (AD) brain with their composition associated with dis-ease etiology. Here, we report a photocatalyst, namely AmyCAT, that selectively binds to amyloid fibrils in AD brain tis-sue and undergoes Dexter energy transfer (DET) to catalyze carbene production for amyloid proximity labeling. First, we design the AmyCAT photocatalyst to generally bind different types of amyloids. Second, we energetically match the DET effect in a 12 × 4 photocatalysts-substrates array to activate diazo substrate into reactive carbene by visible green light (530~545 nm). Further, we demonstrate that the optimal AmyCAT probe catalyzes pan-amyloid protein labeling with 30-fold selectivity over folded counterparts. Mechanistic studies confirm the photocatalytic labeling is indeed via DET pro-cess, which tailors the proximity effect for spatially confined amyloid labeling. Finally, we employ the AmyCAT photo-catalyst to label, enrich and profile amyloid plagues in AD brain tissue, revealing key proteins and pathways associated with AD pathological deposition and etiology.

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Project description:Findings of early cerebral Amyloid-beta deposition in mice after peripheral injection of Amyloid-beta containing brain extracts, and humans following cadaveric human growth hormone treatment raised concerns that Amyloid-beta aggregates and possibly Alzheimer disease (AD) may be transmissible between individuals. Yet, proof that Amyloid-beta actually reaches the brain from the peripheral injection site is lacking. Here, we used a proteomic approach combining stable isotope labeling of mammals and untargeted and targeted mass spectrometry. Specifically, we generated 13C-isotope labeled brain extracts from mice expressing human Amyloid-beta and track 13C-Lys-labeled Amyloid-beta after intraperitoneal administration into young Amyloid betaPP transgenic mice. We detected injected Amyloid-beta in the liver and lymphoid tissues for up to 100 days. In contrast, injected 13C-Lys-labeled Amyloid-beta was not detectable in the brain whereas the mice incorporated 13C-Lys from the donor brain extracts into endogenous Amyloid-beta. Using a highly sensitive and specific proteomic approach, we demonstrated that Amyloid-beta does not reach the brain from the periphery. Our study argues against potential transmissibility of AD while opening new avenues to uncover mechanisms of pathophysiological protein deposition. Please note that corresponding MRM data for this project have been submitted elsewhere.

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