1. EMBER multidimensional spectral microscopy enables quantitative determination of disease- and cell-specific amyloid strains
- Author
-
Yang, Hyunjun, Yuan, Peng, Wu, Yibing, Shi, Marie, D., Christoffer, Tengeiji, Atsushi, Yamanoi, Shigeo, Inoue, Masahiro, DeGrado, William F, and Condello, Carlo
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Brain Disorders ,Aging ,Neurodegenerative ,Alzheimer's Disease ,Acquired Cognitive Impairment ,Neurosciences ,Aetiology ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,2.1 Biological and endogenous factors ,Neurological ,Mice ,Animals ,Humans ,Microscopy ,Alzheimer Disease ,Amyloid beta-Peptides ,Pick Disease of the Brain ,Amyloid ,Brain ,Mice ,Transgenic ,tau Proteins ,Plaque ,Amyloid ,neurodegenerative diseases ,proteins fold ,conformational strain ,fluorescent excitation ,emission ,machine learning ,fluorescent excitation/emission - 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-β (Aβ) deposits in different transgenic mouse models. Our EMBER (excitation multiplexed bright emission recording) imaging method rapidly identifies conformational differences in Aβ 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.
- Published
- 2023