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C-Terminal Threonine Reduces A?43 Amyloidogenicity Compared with A?42.

ABSTRACT: A?43, a product of the proteolysis of the amyloid precursor protein APP, is related to A?42 by an additional Thr residue at the C-terminus. A?43 is typically generated at low levels compared with the predominant A?42 and A?40 forms, but it has been suggested that this longer peptide might have an impact on amyloid-? aggregation and Alzheimer's disease that is out of proportion to its brain content. Here, we report that both A?42 and A?43 spontaneously aggregate into mature amyloid fibrils via sequential appearance of the same series of oligomeric and protofibrillar intermediates, the earliest of which appears to lack ?-structure. In spite of the additional ?-branched amino acid at the C-terminus, A?43 fibrils have fewer strong backbone H-bonds than A?42 fibrils, some of which are lost at the C-terminus. In contrast to previous reports, we found that A?43 spontaneously aggregates more slowly than A?42. In addition, A?43 fibrils are very inefficient at seeding A?42 amyloid formation, even though A?42 fibrils efficiently seed amyloid formation by A?43 monomers. Finally, mixtures of A?42 and A?43 aggregate more slowly than A?42 alone. Both in this A?42/A?43 co-aggregation reaction and in cross-seeding by A?42 fibrils, the structure of the A?43 in the product fibrils is influenced by the presence of A?42. The results provide new details of amyloid structure and assembly pathways, an example of structural plasticity in prion-like replication, and data showing that low levels of A?43 in the brain are unlikely to favorably impact the aggregation of A?42.

SUBMITTER: Chemuru S

PROVIDER: S-EPMC4691432 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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C-Terminal Threonine Reduces Aβ43 Amyloidogenicity Compared with Aβ42.

Chemuru Saketh S Kodali Ravindra R Wetzel Ronald R

Journal of molecular biology 20150626 2 Pt A

Aβ43, a product of the proteolysis of the amyloid precursor protein APP, is related to Aβ42 by an additional Thr residue at the C-terminus. Aβ43 is typically generated at low levels compared with the predominant Aβ42 and Aβ40 forms, but it has been suggested that this longer peptide might have an impact on amyloid-β aggregation and Alzheimer's disease that is out of proportion to its brain content. Here, we report that both Aβ42 and Aβ43 spontaneously aggregate into mature amyloid fibrils via se ...[more]

PMID: 26122432

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Project description:Background: Amyloid beta 1-43 (A?43) may be a useful additional biomarker for diagnosing Alzheimer's disease (AD). We have investigated cerebrospinal fluid (CSF) levels of A?43 in patients with early-onset AD in contrast to levels in late-onset AD. For comparison, in addition to the 'core' biomarkers, several other analytes were also determined [YKL-40, neurofilament light (NF-L), glial fibrillary acidic protein (GFAP), and progranulin]. Material and Methods: Cerebrospinal fluid samples were obtained from patients with early-onset AD (age ? 62, n = 66), late-onset AD (age ? 68, n = 25), and groups of cognitively intact individuals (age ? 62, n = 41, age ? 68, n = 39). Core CSF AD biomarkers [amyloid beta 1-42 (A?42), total tau, phosphorylated tau] were analyzed, as well as levels of A?43 and other analytes, using commercially available enzyme-linked immunosorbent assays. Results: Cerebrospinal fluid A?43 was significantly reduced in early-onset AD compared to late-onset AD (14.8 ± 7.3 vs. 21.8 ± 9.4 pg/ml, respectively), whereas the levels of A?42 in the two AD groups were not significantly different (474.9 ± 142.0 vs. 539.6 ± 159.9 pg/ml, respectively). A?43 and all core biomarkers were significantly altered in patients with AD compared to corresponding controls. NF-L was significantly increased in early-onset AD compared to younger controls, an effect not found between the older groups. Relationships between the A? peptides and tau proteins, YKL-40, NF-L, GFAP and progranulin were also investigated without finding marked associations. However, age-associated increases in levels of tau proteins, YKL-40, NF-L and GFAP were found with respect to age in healthy controls. Results for these other analytes were similar to previously published data. A?43 did not improve diagnostic accuracy in either AD group compared to A?42.DiscussionCerebrospinal fluid A?43, but not A?42 levels, varied significantly with age in patients with AD. If CSF levels of A? peptides reflect amyloid deposition in brain, the possibility arises that there is a difference between A?43 and A?42 deposition in younger compared to older brain. However, the level of A?43 in CSF shows no improvement over A?42 regarding diagnostic accuracy.

Dataset Information

C-Terminal Threonine Reduces A?43 Amyloidogenicity Compared with A?42.

Publications

C-Terminal Threonine Reduces Aβ43 Amyloidogenicity Compared with Aβ42.

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