Biophysical characteristics of lipid-induced Aβ oligomers correlate to distinctive phenotypes in transgenic mice

Autor: Sarah E. Morgan, Dexter N. Dean, Vijayaraghavan Rangachari, Shailendra Dhakal, Kristy D. Dillon, Kelli A. Stockmal, Munir F. Adamo, Yona Levites, Jhinuk Saha
Rok vydání: 2020
Předmět:
0301 basic medicine
Genetically modified mouse
Amyloid
Spectrometry
Mass
Electrospray Ionization
Magnetic Resonance Spectroscopy
Cell Survival
Transgene
Membrane lipids
Mice
Transgenic
Plaque
Amyloid
G(M1) Ganglioside
Fibril
Microscopy
Atomic Force
Biochemistry
Oligomer
Article
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
amyloid‐β
Cell Line
Tumor
Spectroscopy
Fourier Transform Infrared
Genetics
medicine
Animals
oligomers
Molecular Biology
cerebral amyloid angiopathy
Research Articles
Amyloid beta-Peptides
Circular Dichroism
phenotypes
Phosphatidylglycerols
membrane lipids
medicine.disease
Phenotype
Immunohistochemistry
Lipids
Dynamic Light Scattering
030104 developmental biology
chemistry
Cerebral amyloid angiopathy
Alzheimer's disease
Alzheimer disease
030217 neurology & neurosurgery
Biotechnology
Research Article
Zdroj: FASEB J
The FASEB Journal
ISSN: 1530-6860
Popis: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects cognition and memory. Recent advances have helped identify many clinical sub‐types in AD. Mounting evidence point toward structural polymorphism among fibrillar aggregates of amyloid‐β (Aβ) to being responsible for the phenotypes and clinical manifestations. In the emerging paradigm of polymorphism and prion‐like propagation of aggregates in AD, the role of low molecular weight soluble oligomers, which are long known to be the primary toxic agents, in effecting phenotypes remains inconspicuous. In this study, we present the characterization of three soluble oligomers of Aβ42, namely 14LPOs, 16LPOs, and GM1Os with discreet biophysical and biochemical properties generated using lysophosphatidyl glycerols and GM1 gangliosides. The results indicate that the oligomers share some biophysical similarities but display distinctive differences with GM1Os. Unlike the other two, GM1Os were observed to be complexed with the lipid upon isolation. It also differs mainly in detection by conformation‐sensitive dyes and conformation‐specific antibodies, temperature and enzymatic stability, and in the ability to propagate morphologically‐distinct fibrils. GM1Os also show distinguishable biochemical behavior with pronounced neuronal toxicity. Furthermore, all the oligomers induce cerebral amyloid angiopathy (CAA) and plaque burden in transgenic AD mice, which seems to be a consistent feature among all lipid‐derived oligomers, but 16LPOs and GM1Os displayed significantly higher effect than the others. These results establish a correlation between molecular features of Aβ42 oligomers and their distinguishable effects in transgenic AD mice attuned by lipid characteristics, and therefore help bridge the knowledge gap in understanding how oligomer conformers could elicit AD phenotypes.
Databáze: OpenAIRE
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