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Article

The Dynamics of β-Amyloid Proteoforms Accumulation in the Brain of a 5xFAD Mouse Model of Alzheimer’s Disease

1
Emanuel Institute of Biochemical Physics, Russian Academy of Science, 119334 Moscow, Russia
2
Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
3
Engelhardt Institute of Molecular Biology, Russian Academy of Science, 119991 Moscow, Russia
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Skolkovo Institute of Science and Technology, 121205 Moscow, Russia
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Institute of Neuroscience, Lobachevsky State University of Nizhny Novgorod, 603022 Nizhny Novgorod, Russia
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Research Institute of Human Morphology, 117418 Moscow, Russia
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Department of Basic and Applied Neurobiology, Federal Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia
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Mental-Health Clinic No. 1 Named after N.A. Alexeev of Moscow Healthcare Department, 117152 Moscow, Russia
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Neurological Department, Loginov Moscow Clinical Scientific Center, 111123 Moscow, Russia
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V.L. Talrose Institute for Energy Problems of Chemical Physics, N.N. Semenov Federal Center of Chemical Physic, Russian Academy of Sciences, 119334 Moscow, Russia
*
Authors to whom correspondence should be addressed.
Academic Editor: Michael Ugrumov
Int. J. Mol. Sci. 2022, 23(1), 27; https://doi.org/10.3390/ijms23010027
Received: 18 November 2021 / Revised: 16 December 2021 / Accepted: 19 December 2021 / Published: 21 December 2021
Alzheimer’s disease (AD) is the leading cause of dementia among the elderly. Neuropathologically, AD is characterized by the deposition of a 39- to 42-amino acid long β-amyloid (Aβ) peptide in the form of senile plaques. Several post-translational modifications (PTMs) in the N-terminal domain have been shown to increase the aggregation and cytotoxicity of Aβ, and specific Aβ proteoforms (e.g., Aβ with isomerized D7 (isoD7-Aβ)) are abundant in the senile plaques of AD patients. Animal models are indispensable tools for the study of disease pathogenesis, as well as preclinical testing. In the presented work, the accumulation dynamics of Aβ proteoforms in the brain of one of the most widely used amyloid-based mouse models (the 5xFAD line) was monitored. Mass spectrometry (MS) approaches, based on ion mobility separation and the characteristic fragment ion formation, were applied. The results indicated a gradual increase in the Aβ fraction of isoD7-Aβ, starting from approximately 8% at 7 months to approximately 30% by 23 months of age. Other specific PTMs, in particular, pyroglutamylation, deamidation, and oxidation, as well as phosphorylation, were also monitored. The results for mice of different ages demonstrated that the accumulation of Aβ proteoforms correlate with the formation of Aβ deposits. Although the mouse model cannot be a complete analogue of the processes occurring in the human brain in AD, and several of the observed parameters differ significantly from human values supposedly due to the limited lifespan of the model animals, this dynamic study provides evidence on at least one of the possible mechanisms that can trigger amyloidosis in AD, i.e., the hypothesis on the relationship between the accumulation of isoD7-Aβ and the progression of AD-like pathology. View Full-Text
Keywords: Alzheimer’s disease; proteomics; mouse brain; β-amyloid; senile plaques; proteoforms; isoforms; isoD7; post-translational modifications (PTM); mass spectrometry Alzheimer’s disease; proteomics; mouse brain; β-amyloid; senile plaques; proteoforms; isoforms; isoD7; post-translational modifications (PTM); mass spectrometry
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MDPI and ACS Style

Bugrova, A.E.; Strelnikova, P.A.; Indeykina, M.I.; Kononikhin, A.S.; Zakharova, N.V.; Brzhozovskiy, A.G.; Barykin, E.P.; Pekov, S.I.; Gavrish, M.S.; Babaev, A.A.; Kosyreva, A.M.; Morozova, A.Y.; Degterev, D.A.; Mitkevich, V.A.; Popov, I.A.; Makarov, A.A.; Nikolaev, E.N. The Dynamics of β-Amyloid Proteoforms Accumulation in the Brain of a 5xFAD Mouse Model of Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 23, 27. https://doi.org/10.3390/ijms23010027

AMA Style

Bugrova AE, Strelnikova PA, Indeykina MI, Kononikhin AS, Zakharova NV, Brzhozovskiy AG, Barykin EP, Pekov SI, Gavrish MS, Babaev AA, Kosyreva AM, Morozova AY, Degterev DA, Mitkevich VA, Popov IA, Makarov AA, Nikolaev EN. The Dynamics of β-Amyloid Proteoforms Accumulation in the Brain of a 5xFAD Mouse Model of Alzheimer’s Disease. International Journal of Molecular Sciences. 2022; 23(1):27. https://doi.org/10.3390/ijms23010027

Chicago/Turabian Style

Bugrova, Anna E., Polina A. Strelnikova, Maria I. Indeykina, Alexey S. Kononikhin, Natalia V. Zakharova, Alexander G. Brzhozovskiy, Evgeny P. Barykin, Stanislav I. Pekov, Maria S. Gavrish, Alexey A. Babaev, Anna M. Kosyreva, Anna Y. Morozova, Daniil A. Degterev, Vladimir A. Mitkevich, Igor A. Popov, Alexander A. Makarov, and Evgeny N. Nikolaev. 2022. "The Dynamics of β-Amyloid Proteoforms Accumulation in the Brain of a 5xFAD Mouse Model of Alzheimer’s Disease" International Journal of Molecular Sciences 23, no. 1: 27. https://doi.org/10.3390/ijms23010027

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