Mass spectrometry of purified amyloid beta protein in Alzheimer's disease.

Mori, Hiroshi; Takio, Koji; Ogawara, Midori; Selkoe, Dennis J.

doi:10.1016/s0021-9258(18)41896-0

Cited by 415 publications

(88 citation statements)

References 32 publications

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“…Using X-ray diffraction (XRD), we show that L-glu dissolved in water and, upon heating, becomes cyclized, forming a previously unreported structure which resembles L-pyroglutamine and which has been reported to be a component of amyloid-β in the brain ( 13 ) but involves a low-barrier hydrogen-bonded anionic dimer with an ammonium counterion. We have termed the structure, that is, L-pyroglutamine complexed with an ammonium ion, L-pyro-amm.…”

mentioning

confidence: 99%

Short hydrogen bonds enhance nonaromatic protein-related fluorescence

Stephens

Qaisrani

Ruggiero

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Fluorescence in biological systems is usually associated with the presence of aromatic groups. Here, by employing a combined experimental and computational approach, we show that specific hydrogen bond networks can significantly affect fluorescence. In particular, we reveal that the single amino acid L-glutamine, by undergoing a chemical transformation leading to the formation of a short hydrogen bond, displays optical properties that are significantly enhanced compared with L-glutamine itself. Ab initio molecular dynamics simulations highlight that these short hydrogen bonds prevent the appearance of a conical intersection between the excited and the ground states and thereby significantly decrease nonradiative transition probabilities. Our findings open the door to the design of new photoactive materials with biophotonic applications.

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mentioning

confidence: 99%

Short hydrogen bonds enhance nonaromatic protein-related fluorescence

Stephens

Qaisrani

Ruggiero

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…N-terminal truncation of Aβ includes cleavage at residues 2, 4, 5 and 11, each thought to be β-secretase dependent (Vassar et al 1999). Importantly, these N-terminally truncated Aβ forms, such as Aβ3-40/42 and Aβ11-40/42, have been shown to be targets of post-translational modifications such as pyroglutamate modification at glutamic acid 3 or 11; generating key amyloidogenic species (Mori et al 1992;Saido et al 1996). These modified Aβ forms are not secreted by neurons but appear to form in the tissue and may well be Aβ plaque-specific.…”

Section: A β G Ener Ati On From Appmentioning

confidence: 99%

Mass spectrometry analysis of tau and amyloid‐beta in iPSC‐derived models of Alzheimer’s disease and dementia

Arber

Alatza

Leckey

et al. 2021

Journal of Neurochemistry

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Induced pluripotent stem cell (iPSC) technology enables the generation of human neurons in vitro, which contain the precise genome of the cell donor, therefore permitting the generation of disease models from individuals with a disease-associated genotype of interest. This approach has been extensively used to model inherited forms of Alzheimer's disease and frontotemporal dementia. The combination of iPSC-derived neuronal models with targeted mass spectrometry analysis has provided unprecedented insights into the regulation of specific proteins in human neuronal physiology and pathology. For example enabling investigations into tau and APP/Aβ, specifically: protein isoform expression, relative levels of cleavage fragments, aggregated species and functionally critical post-translational modifications. The use of mass spectrometry has enabled a determination of how closely iPSC-derived models recapitulate disease profiles observed in the human brain. This review will highlight the progress to date in studies using iPSCs and mass spectrometry to model Alzheimer's disease and dementia. We go on to convey our optimism, as studies in the near future will make use of this precedent, together with novel techniques such as genome editing and stable isotope labelling, to provide real progress towards an in depth understanding of early neurodegenerative processes and development of novel therapeutic agents.

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“…The AD is originated from the aggregation of β amyloid (abbreviated as Aβ) proteins resulting in the formation of amyloid structures. This Aβ protein present in the brain is categorized into either of two types such as Aβ40 and Aβ42, while the majority is Aβ40 [11]. Despite only two sequence differences between Aβ40 and Aβ42, which are isoleucine and alanine in the C-terminus, Aβ42 has been found to be responsible for the onset of AD [12].…”

Section: Introductionmentioning

confidence: 99%

Different Aggregation Pathways and Structures for Aβ40 and Aβ42 Peptides

2021

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Self-aggregation of amyloid-β (Aβ) peptides has been known to play a vital role in the onset stage of neurodegenerative diseases, indicating the necessity of understanding the aggregation process of Aβ peptides. Despite previous studies on the aggregation process of Aβ peptides, the aggregation pathways of Aβ isoforms (i.e., Aβ40 and Aβ42) and their related structures have not been fully understood yet. Here, we study the aggregation pathways of Aβ40 and Aβ42, and the structures of Aβ40 and Aβ42 aggregates during the process, based on fluorescence and atomic force microscopy (AFM) experiments. It is shown that in the beginning of aggregation process for both Aβ40 and Aβ42, a number of particles (i.e., spherical oligomers) are formed. These particles are subsequently self-assembled together, resulting in the formation of different shapes of amyloid fibrils. Our finding suggests that the different aggregation pathways of Aβ isoforms lead to the amyloid fibrils with contrasting structure.

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Mass spectrometry of purified amyloid beta protein in Alzheimer's disease.

Cited by 415 publications

References 32 publications

Short hydrogen bonds enhance nonaromatic protein-related fluorescence

Short hydrogen bonds enhance nonaromatic protein-related fluorescence

Mass spectrometry analysis of tau and amyloid‐beta in iPSC‐derived models of Alzheimer’s disease and dementia

Different Aggregation Pathways and Structures for Aβ40 and Aβ42 Peptides

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