ABSTRACT
In neurodegenerative diseases, proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. However, there is a need to rapidly identify amyloid conformations in situ. Here, we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid-binding dyes to identify six distinct different conformational strains in vitro, as well as amyloid-ß (Aß) deposits in different transgenic mouse models. Our EMBER (excitation multiplexed bright emission recording) imaging method rapidly identifies conformational differences in Aß and tau deposits from Down syndrome, sporadic and familial Alzheimer's disease human brain slices. EMBER has in situ identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Pick's disease. In future studies, EMBER should enable high-throughput measurements of the fidelity of strain transmission in cellular and animal neurodegenerative diseases models, time course of amyloid strain propagation, and identification of pathogenic versus benign strains.
Subject(s)
Alzheimer Disease , Pick Disease of the Brain , Mice , Animals , Humans , Microscopy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Pick Disease of the Brain/metabolism , Amyloid/metabolism , Brain/metabolism , Mice, Transgenic , tau Proteins/metabolism , Plaque, Amyloid/metabolismABSTRACT
In neurodegenerative diseases proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. However, there is a need to rapidly identify amyloid conformations in situ . Here we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid binding dyes to identify six distinct different conformational strains in vitro , as well as Aß deposits in different transgenic mouse models. Our EMBER (excitation multiplexed bright emission recording) imaging method rapidly identifies conformational differences in Aß and tau deposits from Down syndrome, sporadic and familial Alzheimer's disease human brain slices. EMBER has in situ identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Pick's disease. In future studies, EMBER should enable high-throughput measurements of the fidelity of strain transmission in cellular and animal neurodegenerative diseases models, time course of amyloid strain propagation, and identification of pathogenic versus benign strains. Significance: In neurodegenerative diseases proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. There is a need to rapidly identify these amyloid conformations in situ . Here we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid binding dyes to identify six distinct different conformational strains in vitro , as well as Aß deposits in different transgenic mouse models. Our imaging method rapidly identifies conformational differences in Aß and tau deposits from Down syndrome, sporadic and familial Alzheimer's disease human brain slices. We also identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Pick's disease. These findings will facilitate the identification of pathogenic protein aggregates to guide research and treatment of protein misfolding diseases.
ABSTRACT
The total synthesis of taurospongin A by two new approaches has been achieved where pi-allyltricarbonyliron lactone complexes have been used to control highly stereoselective additions of the nucleophiles to a carbonyl unit located in the side chain of these complexes.
Subject(s)
Alkynes/chemical synthesis , DNA Polymerase beta/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Esters/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , Iron Compounds/chemistry , Lactones/chemistry , Alkynes/pharmacology , Enzyme Inhibitors/pharmacology , Esters/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , StereoisomerismABSTRACT
The synthesis of taurospongin A has been achieved using, as a key step, a pi-allyltricarbonyliron lactone complex to control a highly stereoselective addition of a methyl group to a carbonyl unit located in the side chain of the complex.