Abstract
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.
Highlights
Alzheimer’s disease is the most socially significant neurodegenerative disease of the elderly [1], with about 50 million patients worldwide
The obtained results show the non-linear dynamics of the accumulation of Aβ in 5xFAD mice with age
The isomerization of D7 was one of the dominant modifications of the content, which grows with approximately the same tendency from the early stages of Aβ accumulation to old age and is likely to be an important effector of the enhanced amyloid deposition that begins after 10 months of age
Summary
Alzheimer’s disease is the most socially significant neurodegenerative disease of the elderly [1], with about 50 million patients worldwide. For about 30 years, the formation of Aβ oligomers and plaques was considered the key pathological change that promoted neurotoxicity and induced the further steps of the pathogenic cascade, which involves tau hyperphosphorylation and neuroinflammation [3,4,5,6,7]. Of all Aβ proteoforms, Aβ with the isomerization of D7 (isoD7-Aβ) deserves special attention since its accumulation correlates with the key pathological changes in amyloidosis: isoD7-Aβ is more prone to zinc-dependent oligomerization [29]; it exerts higher neurotoxicity and receptor toxicity in vitro [30,31]; and it is able to induce plaque formation in vivo [32]. The dynamic study of isoD7 accumulation in the brain may further clarify whether its abundance in amyloid plaques correlates with the increased aggregation, or whether this is the result of spontaneous Asp-isoAsp conversions in aggregated Aβ [19]. Tanhde oAbDtaipnreodgrreesssuilotns ,suwgagsessttutdhiaetdisuosDin7gAMβAaLnDdIoTtOheFr/pTrOoFte, oTfIoMrmS-Ts OcoFrrMelSa,taenwdiMthSt/hMe fSo.rTmhaetoiobntaoinfeAdβredseupltosssitusg. gest that isoD7-Aβ and other proteoforms correlate with the formation of Aβ deposits
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