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Site-specific glycation of A?1-42 affects fibril formation and is neurotoxic.

ABSTRACT: A?1-42 is involved in Alzheimer's disease (AD) pathogenesis and is prone to glycation, an irreversible process where proteins accumulate advanced glycated end products (AGEs). N ?-(Carboxyethyl)lysine (CEL) is a common AGE associated with AD patients and occurs at either Lys-16 or Lys-28 of A?1-42. Methyglyoxal is commonly used for the unspecific glycation of A?1-42, which results in a complex mixture of AGE-modified peptides and makes interpretation of a causative AGE at a specific amino acid residue difficult. We address this issue by chemically synthesizing defined CEL modifications on A?1-42 at Lys-16 (A?-CEL16), Lys-28 (A?-CEL28), and Lys-16 and -28 (A?-CEL16&28). We demonstrated that double-CEL glycations at Lys-16 and Lys-28 of A?1-42 had the most profound impact on the ability to form amyloid fibrils. In silico predictions indicated that A?-CEL16&28 had a substantial decrease in free energy change, which contributes to fibril destabilization, and a increased aggregation rate. Single-CEL glycations at Lys-28 of A?1-42 had the least impact on fibril formation, whereas CEL glycations at Lys-16 of A?1-42 delayed fibril formation. We also tested these peptides for neuronal toxicity and mitochondrial function on a retinoic acid-differentiated SH-SY5Y human neuroblastoma cell line (RA-differentiated SH-SY5Y). Only A?-CEL16 and A?-CEL28 were neurotoxic, possibly through a nonmitochondrial pathway, whereas A?-CEL16&28 showed no neurotoxicity. Interestingly, A?-CEL16&28 had depolarized the mitochondrial membrane potential, whereas A?-CEL16 had increased mitochondrial respiration at complex II. These results may indicate mitophagy or an alternate route of metabolism, respectively. Therefore, our results provides insight into potential therapeutic approaches against neurotoxic CEL-glycated A?1-42.

SUBMITTER: Ng J

PROVIDER: S-EPMC6552435 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Site-specific glycation of Aβ1-42 affects fibril formation and is neurotoxic.

Ng Jin J Kaur Harveen H Collier Thomas T Chang Kevin K Brooks Anna E S AES Allison Jane R JR Brimble Margaret A MA Hickey Anthony A Birch Nigel P NP

The Journal of biological chemistry 20190417 22

Aβ1-42 is involved in Alzheimer's disease (AD) pathogenesis and is prone to glycation, an irreversible process where proteins accumulate advanced glycated end products (AGEs). <i>N</i><sup>ϵ</sup>-(Carboxyethyl)lysine (CEL) is a common AGE associated with AD patients and occurs at either Lys-16 or Lys-28 of Aβ1-42. Methyglyoxal is commonly used for the unspecific glycation of Aβ1-42, which results in a complex mixture of AGE-modified peptides and makes interpretation of a causative AGE at a spec ...[more]

PMID: 30996005

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Project description:Proteolytic fragments of amyloid and post-translational modification of tau species in Cerebrospinal fluid (CSF) as well as cerebral amyloid deposition are important biomarkers for Alzheimer's Disease. We conducted genome-wide association study to identify genetic factors influencing CSF biomarker level, cerebral amyloid deposition, and disease progression. The genome-wide association study was performed via a meta-analysis of two non-overlapping discovery sample sets to identify genetic variants other than APOE ε4 predictive of the CSF biomarker level (Aβ1-42, t-Tau, p-Tau181P, t-Tau:Aβ1-42 ratio, and p-Tau181P:Aβ1-42 ratio) in patients enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Loci passing a genome-wide significance threshold of P < 5 x 10-8 were followed-up for replication in an independent sample set. We also performed joint meta-analysis of both discovery sample sets together with the replication sample set. In the discovery phase, we identified variants in FRA10AC1 associated with CSF Aβ1-42 level passing the genome-wide significance threshold (directly genotyped SNV rs10509663 PFE = 1.1 x 10-9, imputed SNV rs116953792 PFE = 3.5 x 10-10), rs116953792 (Pone-sided = 0.04) achieved replication. This association became stronger in the joint meta-analysis (directly genotyped SNV rs10509663 PFE = 1.7 x 10-9, imputed SNV rs116953792 PFE = 7.6 x 10-11). Additionally, we identified locus 15q21 (imputed SNV rs1503351 PFE = 4.0 x 10-8) associated with CSF Aβ1-42 level. No other variants passed the genome-wide significance threshold for other CSF biomarkers in either the discovery sample sets or joint analysis. Gene set enrichment analyses suggested that targeted genes mediated by miR-33, miR-146, and miR-193 were enriched in various GWAS analyses. This finding is particularly important because CSF biomarkers confer disease susceptibility and may be predictive of the likelihood of disease progression in Alzheimer's Disease.

Dataset Information

Site-specific glycation of A?1-42 affects fibril formation and is neurotoxic.

Publications

Site-specific glycation of Aβ1-42 affects fibril formation and is neurotoxic.

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