Dataset Information

Amyloid Structural Changes Studied by Infrared Microspectroscopy in Bigenic Cellular Models of Alzheimer's Disease.

ABSTRACT: Alzheimer's disease affects millions of lives worldwide. This terminal disease is characterized by the formation of amyloid aggregates, so-called amyloid oligomers. These oligomers are composed of β-sheet structures, which are believed to be neurotoxic. However, the actual secondary structure that contributes most to neurotoxicity remains unknown. This lack of knowledge is due to the challenging nature of characterizing the secondary structure of amyloids in cells. To overcome this and investigate the molecular changes in proteins directly in cells, we used synchrotron-based infrared microspectroscopy, a label-free and non-destructive technique available for in situ molecular imaging, to detect structural changes in proteins and lipids. Specifically, we evaluated the formation of β-sheet structures in different monogenic and bigenic cellular models of Alzheimer's disease that we generated for this study. We report on the possibility to discern different amyloid signatures directly in cells using infrared microspectroscopy and demonstrate that bigenic (amyloid-β, α-synuclein) and (amyloid-β, Tau) neuron-like cells display changes in β-sheet load. Altogether, our findings support the notion that different molecular mechanisms of amyloid aggregation, as opposed to a common mechanism, are triggered by the specific cellular environment and, therefore, that various mechanisms lead to the development of Alzheimer's disease.

SUBMITTER: Paulus A

PROVIDER: S-EPMC8037084 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Amyloid Structural Changes Studied by Infrared Microspectroscopy in Bigenic Cellular Models of Alzheimer's Disease.

Paulus Agnes A Engdahl Anders A Yang Yiyi Y Boza-Serrano Antonio A Bachiller Sara S Torres-Garcia Laura L Svanbergsson Alexander A Garcia Megg G MG Gouras Gunnar K GK Li Jia-Yi JY Deierborg Tomas T Klementieva Oxana O

International journal of molecular sciences 20210326 7

Alzheimer's disease affects millions of lives worldwide. This terminal disease is characterized by the formation of amyloid aggregates, so-called amyloid oligomers. These oligomers are composed of β-sheet structures, which are believed to be neurotoxic. However, the actual secondary structure that contributes most to neurotoxicity remains unknown. This lack of knowledge is due to the challenging nature of characterizing the secondary structure of amyloids in cells. To overcome this and investiga ...[more]

PMID: 33810433

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Project description:Alzheimer’s Disease (AD) is the most common cause of age-related dementia and the sixth leading cause of death in the United States. AD neuropathology is primarily characterized by the accumulation of extracellular beta-amyloid (Aβ) plaques and intraneuronal neurofibrillary tau tangles. In addition to these hallmark AD pathologies, many other important pathological changes occur in the brains of AD patients, including synaptic and neuronal loss and neuroinflammation. Most recently, genome-wide association studies (GWAS) have provided substantial new evidence that immune dysfunction may contribute to the development and progression of AD. To date over 60 GWAS loci have been identified and almost two thirds of these genes are highly expressed in microglia, the resident innate immune cell of the brain. These genetic discoveries have in turn inspired many new studies of microglial biology and the role of these cells in AD. In contrast, the role of the adaptive immunity in AD remains understudied, despite evidence that many of AD risk genes are also highly expressed in T and B cells. To investigate the role of T cell infiltration in AD, we examined T cells from immune-deficient AD mice via bone marrow transplantation studies using flow cytometry and immunohistochemistry; and from immune-intact transgenic AD model mice using flow cytometry, immunohistochemistry, and single-cell RNA sequencing. Our experiments demonstrate that multiple T cell subtypes infiltrate the AD brain, and that effector memory CD8 T cells are specifically enriched in response to Aβ pathology or a combination of Aβ and tau pathologies. Single-cell sequencing analysis revealed high expression of over 40 AD risk genes between several T cell sub-populations, implying a need for more research of these T cell phenotypes in AD development. Additionally, T-cell receptor (TCR) sequencing revealed increased clonal expansion of T cells from mice that developed Aβ pathology or Aβ and tau pathology, suggesting amyloid-driven recruitment and clonal expansion of T cells in these mice. Ultimately, this study demonstrates the crucial importance of investigating the role of T cells in AD and provides a guide for future experiments to continue to enhance our understanding of AD immunology.

Project description:Key events in postnatal brain development, such as neuronal migration, synaptogenesis, and myelination, shape the adult brain. These events are reflected in changes in gray and white matter (GM and WM) occurring during this period. Therefore, precise knowledge of GM and WM composition in perinatal brain development is crucial to characterizing brain formation as well as the neurodevelopmental disruption observed in diseases such as autism and schizophrenia. In this study, we combined histochemical and immunohistochemical staining with biochemical and biophysical analyses using Fourier transform infrared (IR) microspectroscopy (μFTIR) to better understand the chemical changes during postnatal developmental myelination. For this purpose, we analyzed the GM and WM in the mouse brain and cerebellum (strain C57BL/6) from postnatal day 0 (P0) to day P28 and established presumed correlations between staining and IR data. IR spectra allowed the (i) quantification of lipid and protein content through the CH2/amide I ratio, (ii) determination of chemical characteristics of lipids, such as the presence of unsaturated bonds in the carbonate chain or carbonyls from ester groups in the polar head, and (iii) determination of the protein secondary structure (α-helix and intramolecular β-sheets). The results indicate that the increase in the CH2/amide I ratio calculated from the μFTIR data correlates well with lipid histochemical staining. IR data indicated a change in the lipid composition in WM since carbonyl and unsaturated olefinic groups do not increase when lipids accumulate during myelination. Our correlation analysis between IR data and immunohistochemical staining of myelin-associated proteins revealed that myelin oligodendrocyte protein correlated well with lipid accumulation, while myelin basic protein appeared before lipid modifications, which indicated that myelin-associated proteins and lipid deposition were not synchronic. These events were related to a decrease in the intramolecular β/α protein ratio. Our results indicate that lipids and proteins in WM substantially change their composition due to primary myelination, and according to results obtained from staining, these modifications are better described by lipid histochemical staining than by immunohistochemistry against myelin-related proteins. In conclusion, μFTIR can be a useful technique to study WM during perinatal development and provide detailed information about alterations in the chemical composition related to neurodevelopmental diseases.

Dataset Information

Amyloid Structural Changes Studied by Infrared Microspectroscopy in Bigenic Cellular Models of Alzheimer's Disease.

Publications

Amyloid Structural Changes Studied by Infrared Microspectroscopy in Bigenic Cellular Models of Alzheimer's Disease.

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