Modified Amyloids
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Introduction
The pathology of Alzheimer’s disease is closely related to the processing of amyloid precursor protein (APP), resulting in the formation of a variety of amyloid-β (Aβ) peptides. They are found in insolent plaques as insoluble aggregates, a histopathological hallmark of the disease. These peptides are also present in the interstitial and cerebrospinal fluid in soluble, predominantly monomeric and dimeric forms. Due to the combination of several enzyme activities during APP processing, Aβ peptides are present in multiple isoforms with different N-terminus and C-terminus. These peptides include a portion of the proximal and transmembrane domains of APP. In addition to size differences, post-translational modifications of Aβ-including oxidation, phosphorylation, nitrification, racemization, isomerization, pyroglutamylation and glycosylation - produce excessive peptides with different physiological and pathological properties that can regulate disease progression.
Mechanism of action
Most AD cases were sporadic, while Aβ peptide production did not change. Thus, the propensity to form aggregates and toxic substances may be driven by factors other than those produced by certain Aβ peptides. Several post-translational modifications (PTM) have been discovered that generally increase the rate of aggregation of Aβ. Some of these modifications, such as oxidation and nitration, are apparently caused by the inflammatory environment of a component of AD. The most significant oxidative change site in Aβ is the 35-position (Met35) methionine. Increased oxidative stress has been described in the brains of patients with mild cognitive impairment and AD. PTMs can function as a molecular switch to evoke cellular responses, but one should consider that they may also be a result of protein aging that is random and without any physiological impact.
Application of Modified Amyloids
From too many Aβ species, some are produced very early in the APP process, some are modified immediately afterwards, or some are found or produced in some cells or extracellular compartments, and some are actually markers for the species’s slow to non-existent transformation. A polypeptide in an amyloid plaque. Certain Aβ regions contribute significantly to their properties, such as N-terminal truncations, and certain amino acids are hotspots for PTM. Some of these species may be excellent diagnostic markers or therapeutic targets in the future.
References
- Knowles, T. P., & Mezzenga, R. (2016). Amyloid fibrils as building blocks for natural and artificial functional materials. Advanced Materials, 28(31), 6546-6561.
- Soto, C., Estrada, L., & Castilla, J. (2006). Amyloids, prions and the inherent infectious nature of misfolded protein aggregates. Trends in biochemical sciences, 31(3), 150-155.
- Kummer, M. P., & Heneka, M. T. (2014). Truncated and modified amyloid-beta species. Alzheimer's research & therapy, 6(3), 28.
