Chiral Interface of Amyloid Beta (Aβ): Relevance to Protein Aging, Aggregation and Neurodegeneration

Abstract

Biochirality is the subject of distinct branches of science, including biophysics, biochemistry, the stereochemistry of protein folding, neuroscience, brain functional laterality and bioinformatics. At the protein level, biochirality is closely associated with various post-translational modifications (PTMs) accompanied by the non-equilibrium phase transitions (PhTs NE ). PTMs NE support the dynamic balance of the prevalent chirality of enzymes and their substrates. The stereoselective nature of most biochemical reactions is evident in the enzymatic (Enz) and spontaneous (Sp) PTMs (PTMs Enz and PTMs Sp ) of proteins. Protein chirality, which embraces biophysics and biochemistry, is a subject of this review. In this broad field, we focus attention to the amyloid-beta (Aβ) peptide, known for its essential cellular functions and associations with neuropathology. The widely discussed amyloid cascade hypothesis (ACH) of Alzheimer's disease (AD) states that disease pathogenesis is initiated by the oligomerization and subsequent aggregation of the Aβ peptide into plaques. The racemization-induced aggregation of protein and RNA have been extensively studied in the search for the contribution of spontaneous stochastic stereo-specific mechanisms that are common for both kinds of biomolecules. The failure of numerous Aβ drug-targeting therapies requires the reconsolidation of the ACH with the concept of PTMs Sp . The progress in methods of chiral discrimination can help overcome previous limitations in the understanding of AD pathogenesis. The primary target of attention becomes the network of stereospecific PTMs that affect the aggregation of many pathogenic agents, including Aβ. Extensive recent experimental results describe the truncated, isomerized and racemized forms of Aβ and the interplay between enzymatic and PTMs Sp . Currently, accumulated data suggest that non-enzymatic PTMs Sp occur in parallel to an existing metabolic network of enzymatic pathways, meaning that the presence and activity of enzymes does not prevent non-enzymatic reactions from occurring. PTMs Sp impact the functions of many proteins and peptides, including Aβ. This is in logical agreement with the silently accepted racemization hypothesis of protein aggregation (RHPA). Therefore, the ACH of AD should be complemented by the concept of PTMs Sp and RHPA.

Interactions of Amyloid-β with Membrane Proteins

“…5–10% of the total number of amino acids building Aβ in senile plaques was confirmed in AD patients [ 28 ]. The racemization of Aβ 1–40 in the D residue of Ser 26 is assumed to play an important role in AD pathogenesis [ 28 , 32 , 35 ]. Racemization of Ser 26 leads to the formation of non-fibrillar, soluble [D-Ser 26 ]Aβ 1–40 from fibrillary, insoluble Aβ of amyloid deposits.…”

Racemization in Post-Translational Modifications Relevance to Protein Aging, Aggregation and Neurodegeneration: Tip of the Iceberg

“…Recently the theoretical framework was introduced for the use of D-amino acids as a universal tool to the exploration the aggregation pathways of IDPs [ 11 ]. The study of non-equilibrium phase transition [ 22 ] in IDP and the role of L- D- AAs substitution is a matter of urgency. The rate of racemization of amino acids (AAs) is temperature dependent and under influence of external physical fields can be altered in the order of 10 4 –10 5 .…”

“…The transport of proteins from the cytosol to the membrane phosphor-lipid or nuclear environment is accompanied by conformational phase transitions. The interplay of the thermodynamic equilibrium and the fundamentally non-equilibrium nature of cellular biochemistry constitutes the basis for the non-equilibrium phase transitions [ 21 , 22 , 33 , 42 ].…”

“…( VI. From a physical point of view, racemization is considered because of phase transition between the R and S enantiomers [ 22 , 86 ]).…”

d-Amino Acids and pLG72 in Alzheimer’s Disease and Schizophrenia

“…Since Aβ can induce SR expression and D-serine release in microglia [89], it is not surprising that the D-serine level increases along with AD progression. In addition, the racemization of protein-bound amino acids is significant in protein aging and aggregation, which contributes to neurodegeneration [102]. The Aβ1-40, racemized at Ser26, is soluble and susceptible to proteolysis, which converts into toxic fragments [103], and this racemized amyloid-β is associated with AD pathogenesis [104].…”