Concerted action of dipeptidyl peptidase IV and glutaminyl cyclase results in formation of pyroglutamate-modified amyloid peptides in vitro

Antonyan, Alvard; Schlenzig, Dagmar; Schilling, Stephan; Naumann, Marcel; Sharoyan, Svetlana; Mardanyan, Sona; Demuth, Hans‐Ulrich

doi:10.1016/j.neuint.2017.12.001

Cited by 21 publications

(17 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Implication of a member of the dipeptidyl peptidase family enzymes (DPP) has been previously suggested (62). Recently, in vitro experiments using MALDI-TOF MS applications have pointed out the possible implication of DPPIV in A␤3-X formation (63). Interestingly, A␤40 peptide appeared to be the more prone to DPPIV truncation compared with A␤42.…”

Section: A␤3-x and Pe3-xa␤mentioning

confidence: 98%

Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?

Dunys

Valverde

Checler

2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

The histopathology of Alzheimer's disease (AD) is characterized by neuronal loss, neurofibrillary tangles, and senile plaque formation. The latter results from an exacerbated production (familial AD cases) or altered degradation (sporadic cases) of 40/42-amino acid-long β-amyloid peptides (Aβ peptides) that are produced by sequential cleavages of Aβ precursor protein (βAPP) by β- and γ-secretases. The amyloid cascade hypothesis proposes a key role for the full-length Aβ42 and the Aβ40/42 ratio in AD etiology, in which soluble Aβ oligomers lead to neurotoxicity, tau hyperphosphorylation, aggregation, and, ultimately, cognitive defects. However, following this postulate, during the last decade, several clinical approaches aimed at decreasing full-length Aβ42 production or neutralizing it by immunotherapy have failed to reduce or even stabilize AD-related decline. Thus, the Aβ peptide (Aβ40/42)-centric hypothesis is probably a simplified view of a much more complex situation involving a multiplicity of APP fragments and Aβ catabolites. Indeed, biochemical analyses of AD brain deposits and fluids have unraveled an Aβ peptidome consisting of additional Aβ-related species. Such Aβ catabolites could be due to either primary enzymatic cleavages of βAPP or secondary processing of Aβ itself by exopeptidases. Here, we review the diversity of N- and C-terminally truncated Aβ peptides and their biosynthesis and outline their potential function/toxicity. We also highlight their potential as new pharmaceutical targets and biomarkers.

show abstract

Section: A␤3-x and Pe3-xa␤mentioning

confidence: 98%

Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?

Dunys

Valverde

Checler

2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…For example, N-truncated Aβ 5-X is mainly produced from the caspase-cleaved form of APP and not from full-length Aβ (Murayama et al, 2007 ). Another potential alternative may be the generation the Aβ4-x peptide, a sequential cleavage of full-length Aβ by aminopeptidase A, meprin-β or dipeptidyl-peptidases (Sevalle et al, 2009 ; Antonyan et al, 2018 ; Schlenzig et al, 2018 ; Valverde et al, 2021 ). At least theoretically, Aβ 4-x could be derived from Aβ 2-x or Aβ 3-x peptide ( Figure 1B ).…”

Section: Aβ 4-x Can Be Generated By Enzymatic Cleavagementioning

confidence: 99%

N-Truncated Aβ Starting at Position Four—Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer’s Disease

Bayer

2021

Front. Aging Neurosci.

View full text Add to dashboard Cite

The discussion of whether amyloid plaque Aβ is a valid drug target to fight Alzheimer’s disease (AD) has been a matter of scientific dispute for decades. This question can only be settled by successful clinical trials and the approval of disease-modifying drugs. However, many clinical trials with antibodies against different regions of the amyloid Aβ peptide have been discontinued, as they did not meet the clinical endpoints required. Recently, passive immunization of AD patients with Donanemab, an antibody directed against the N-terminus of pyroglutamate Aβ, showed beneficial effects in a phase II trial, supporting the concept that N-truncated Aβ is a relevant target for AD therapy. There is long-standing evidence that N-truncated Aβ variants are the main variants found in amyloid plaques besides full-length Aβ1–42, t, therefore their role in triggering AD pathology and as targets for drug development are of interest. While the contribution of pyroglutamate Aβ3–42 to AD pathology has been well studied in the past, the potential role of Aβ4–42 has been largely neglected. The present review will therefore focus on Aβ4–42 as a possible drug target based on human and mouse pathology, in vitro and in vivo toxicity, and anti-Aβ4-X therapeutic effects in preclinical models.

show abstract

“…It should be noted that DPP4 was documented as the rate-limiting enzyme yielding E3-Aβ amenable to cyclization by QC. These concerted enzymatic events have been previously documented in vitro ( 23 ).…”

Section: Discussionmentioning

confidence: 57%

“…This is likely due to the reduction of pE3-Aβ. Thus, it has been shown that very low amounts of pE3-42Aβ are sufficient to serve as Aβ42 seed ( 47 ), accelerate its aggregation ( 23 ), and thereby, the occurrence of plaques.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dipeptidyl peptidase 4 contributes to Alzheimer’s disease–like defects in a mouse model and is increased in sporadic Alzheimer’s disease brains

Valverde

Dunys

Lorivel

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

Please cite this article as: RRH: DPP4 contributes to Alzheimer's disease This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

Concerted action of dipeptidyl peptidase IV and glutaminyl cyclase results in formation of pyroglutamate-modified amyloid peptides in vitro

Cited by 21 publications

References 30 publications

Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?

Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?

N-Truncated Aβ Starting at Position Four—Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer’s Disease

Dipeptidyl peptidase 4 contributes to Alzheimer’s disease–like defects in a mouse model and is increased in sporadic Alzheimer’s disease brains

Contact Info

Product

Resources

About