Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer’s disease

Abstract

A proposed key event in the pathogenesis of Alzheimer’s disease (AD) is the formation of neurotoxic amyloid β (Aβ) oligomers and amyloid plaques in specific brain regions that are affected by the disease. The main plaque component is the 42 amino acid isoform of Aβ (Aβ1-42), which is thought to initiate plaque formation and AD pathogenesis. Numerous isoforms of Aβ, e.g., Aβ1-42, Aβ1-40 and the 3-pyroglutamate derivate of Aβ3-42 (pGluAβ3-42), have been detected in the brains of sporadic AD (SAD) and familial AD (FAD) subjects. However, the relative importance of these isoforms in the pathogenesis of AD is not fully understood. Here, we report a detailed study using immunoprecipitation in combination with mass spectrometric analysis to determine the Aβ isoform pattern in the cerebellum, cortex and hippocampus in AD, including subjects with a mutation in the presenilin (M146V) or amyloid precursor protein (KM670/671NL) genes, SAD subjects and non-demented controls. We show that the dominating Aβ isoforms in the three different brain regions analyzed from control, SAD, and FAD are Aβ1-42, pGluAβ3-42, Aβ4-42 and Aβ1-40 of which Aβ1-42 and Aβ4-42 are the dominant isoforms in the hippocampus and the cortex in all groups analyzed, controls included. No prominent differences in Aβ isoform patterns between FAD and SAD patients were seen, underscoring the similarity in the amyloid pathology of these two disease entities.

A comparative analysis of the aggregation behavior of amyloid‐β peptide variants

“…FAD mutations can thus either inhibit or induce aggregation depending on the suitability of the replacing amino acid to accommodate an amyloidogenic or aggregated structure. Molecular dynamics simulations have suggested the depletion of the E22-K28 salt bridge to explain the enhanced aggregation of E22Q Ab , while the switch of a bend motif to a turn in the region Ab [22][23][24][25][26][27][28] could result in slower aggregation of the D23N Ab 1-42 mutant [25]. Overall fibril morphology is however not affected, as has been shown previously for a subset of FAD mutants [23].…”

Site-specific characterization of threonine, serine, and tyrosine glycosylations of amyloid precursor protein/amyloid β-peptides in human cerebrospinal fluid

“…We propose that in the presence of a Tyr10 O-glycosylation γ-secretase-dependent cleavage is modified, such that instead of cleavage at amino acid residues 40-42, the residues at 15-20 become the preferred cleavage sites (9,46). This hypothesis is based on the presence and structures of the Aβ1-X series of Tyr10 O-glycosylated peptides (Aβ1-15, 1-16, 1-17, 1-18, 1-19, and [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and the lack of glycosylated Aβ1-40/42 peptides in CSF. However, the appearance of Aβ peptides in CSF is the result of both complex production and clearance mechanisms (17).…”

“…In the amyloidogenic pathway β-and γ-secretases cleave APP into several Aβ isoforms (SI Appendix, Fig. S1) of which the 42 amino acid isoform (Aβ1-42) is one of the major constituents of amyloid plaques in the brains of AD patients (13). APP may also be cleaved in the middle of the Aβ1-42 sequence by α-secretase, precluding the formation of Aβ1-42 and thus considered to protect from amyloid deposition in the brain (9).…”

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

“…Later immunohistochemical studies of human brain identified A␤ pE3 as a major component of A␤ plaques (12,13). More recently, immunoprecipitation in combination with mass spectrometry confirmed A␤ pE3-42 as a dominant A␤ isoform in the hippocampus and cortex of AD patients (14,15). Saido et al (12) suggested that removal of N-terminal amino acids 1 and 2 of A␤ might be carried out by a hypothetical amino or dipeptidyl peptidase(s), followed by a putative glutamate cyclization activity.…”