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  • A deposits irrespective of their topographical location with

    2019-07-30

    Aβ deposits, irrespective of their topographical location within the brain, are poorly soluble and highly heterogeneous, containing a variety of post-translational modifications that include, among others, isomerization and racemization of aspartates, cyclation of N-terminal glutamates, oxidation of methionine and abundant N- and C-terminal truncations [11], [12]. It is well known that post-translational modifications play a key role in functional proteomics by dramatically increasing the proteome diversity and modulating many aspects of cell function [13]. The importance of Aβ modifications for the process of amyloidogenesis as well as the mechanisms that drive these enzymatic and non-enzymatic modifications are currently under increased scrutiny. One of the most studied protein modifications is the formation of N-terminal pyroglutamate (pE) which has been reported in N-terminally truncated forms of Aβ, specifically pE3Aβ and pE11Aβ. The additional loss of a negative charge occurring as a result of the cyclation of glutamate increases the β-sheet content, aggregation propensity, hydrophobicity, and resistance to enzymatic degradation of the Aβ fragments [14], [15] suggesting a contribution of these species to the disease process. In this sense, pE-modified forms of Aβ have been shown to be more neurotoxic than full-length, unmodified Aβ [16], [17], [18], [19] and to be more abundant in the AD GSK1838705A compared to cognitively intact age-matched controls, further highlighting their biological relevance [20], [21], [22], [23], [24]. Spontaneous, non-enzymatic isomerization at asparagine and aspartate residues was described early on in parenchymal plaque core preparations [25]. More recently, partial aspartate isomerization at positions 1, 7 and 23 has been biochemically identified in parenchymal and cerebrovascular deposits of the Iowa Aβ variant (AβD23N) [12]. This post-translational modification in conjunction with the D23N mutation largely contribute to the enhanced aggregation/fibrillization and cell toxicity properties of the Iowa mutant, triggering apoptotic pathways with mitochondrial engagement and cytochrome c release in both neuronal and microvascular endothelial cells [26]. Oxidative damage due to accumulation of reactive oxygen species (ROS) in AD is known to be an important contributor of the disease pathogenesis. However, oxidation of Aβ at Methionine 35 seems to play a more complex role in the process of oligomerization than initially thought; while the formation of the reversible sulfoxide derivative has been shown to prevent oligomerization and neurotoxicity, the poorly reversible formation of the sulfone derivative produces the opposite effect, suggesting a protective role of mild oxidative conditions [27], [28]. In addition to the abundance of pE-, iso-Asp and oxidated Aβ species, numerous N- and C-terminal truncations significantly contribute to the molecular heterogeneity of the Aβ deposits. Besides the intact Aβ peptides generated by the combined action of BACE1 and γ-secretase – starting at the aspartate residue at position 1 and ending at amino acids 38/40/42 – different truncated Aβ species have been identified in cellular and animal models as well as in AD patients [15], [29], [30], [31], [32], [33], [34], [35], [36], likely generated by the action of a number of Aβ-degrading enzymes, among them neprylisin, insulin degrading- and endothelin converting-enzymes, plasmin and matrix metalloproteases [37], [38], [39], [40], [41], [42]. Reduced levels and/or decreased catalytic activity of these Aβ-degrading enzymes as a result of age, genetic factors, and specific disease conditions have been proposed to affect Aβ accumulation, an issue well documented in murine models in which gene deletion of different proteases translate into increased levels of Aβ deposition [39], [40], [43]. N-terminal truncated Aβ peptides, particularly species beginning with phenylalanine residue at position 4 of Aβ (Aβ4–42), were reported three decades ago [6] and the limited studies available seem to indicate their relative abundance in patients with AD, Down's syndrome, and vascular dementia [44], [45], [46]. Numerous C-terminal truncations have also been described as components of brain deposits although the limited studies reported for these species have been primarily dedicated to their occurrence in the heterogeneous CSF Aβ profile [30], [47], [48]. We have recently described that the action of the matrix metalloproteases MMP-2 and MMP-9 generates one of the most relevant C-terminally truncated fragments, Aβ1–34 [41]. Recent work has also demonstrated that this truncated peptide is capable of being originated through BACE1 cleavage and illustrated the presence of Aβ1–34 in transfected HEK293 cells simultaneously overexpressing APP and BACE1, as well as in brain tissues of 3xTg mice, a model artificially engineered with mutations associated with FAD and FTDP-17 diseases concurrently (APP Swedish, PSEN1 M146V and Tau P301L transgenes) [49]. More studies using additional APP Tg models as well as human AD cases are required to determine the in vivo relevance of these truncation.