Abstract: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 prod… Show more
“…DPP4 removes X-Pro/Ala N-terminal dipeptides (where X is any amino acid) from substrates of <100 residues, including glucagon-like peptide-1 and amyloid-β peptides ( 31 , 34 ), as long as the third residue is not Pro (i.e., X-Pro/Ala↓ . Internal cleavage of PrP C , a protein of >200 residues, is not in line with the canonical function of DPP4, but certain DPP4 inhibitors target FAP as well; indeed, the most effective compounds in our study, linagliptin and talabostat, reportedly inhibit FAP with IC 50 s of 370 nM and 70 nM, respectively, which are closer to the values we observed than the relatively consistent low-nanomolar potencies that the DPP4 inhibitors display toward DPP4 itself ( 34 , 35 ). Moreover, in addition to its DPP4-like exopeptidase activity, FAP acts as an endopeptidase favoring the sequence Gly–Pro↓ ( 30 , 36 , 37 )—motifs present in multiple copies within the mutated S3 PrP OR domain (Gly–Gly–Gly/Ser→Gly–Pro–Gly/Ser).…”
The cellular prion protein (PrP
C
) converts to alternatively folded pathogenic conformations (PrP
Sc
) in prion infections and binds neurotoxic oligomers formed by amyloid-β α-synuclein, and tau. β-Endoproteolysis, which splits PrP
C
into N- and C-terminal fragments (N2 and C2, respectively), is of interest because a protease-resistant, C2-sized fragment (C2
Sc
) accumulates in the brain during prion infections, seemingly comprising the majority of PrP
Sc
at disease endpoint in mice. However, candidates for the underlying proteolytic mechanism(s) remain unconfirmed in vivo. Here, a cell-based screen of protease inhibitors unexpectedly linked type II membrane proteins of the S9B serine peptidase subfamily to PrP
C
β-cleavage. Overexpression experiments in cells and assays with recombinant proteins confirmed that fibroblast activation protein (FAP) and its paralog, dipeptidyl peptidase-4 (DPP4), cleave directly at multiple sites within PrP
C
’s N-terminal domain. For wild-type mouse and human PrP
C
substrates expressed in cells, the rank orders of activity were human FAP ~ mouse FAP > mouse DPP4 > human DPP4 and human FAP > mouse FAP > mouse DPP4 >> human DPP4, respectively. C2 levels relative to total PrP
C
were reduced in several tissues from FAP-null mice, and, while knockout of DPP4 lacked an analogous effect, the combined DPP4/FAP inhibitor linagliptin, but not the FAP-specific inhibitor SP-13786, reduced C2
Sc
and total PrP
Sc
levels in two murine cell-based models of prion infections. Thus, the net activity of the S9B peptidases FAP and DPP4 and their cognate inhibitors/modulators affect the physiology and pathogenic potential of PrP
C
.
“…DPP4 removes X-Pro/Ala N-terminal dipeptides (where X is any amino acid) from substrates of <100 residues, including glucagon-like peptide-1 and amyloid-β peptides ( 31 , 34 ), as long as the third residue is not Pro (i.e., X-Pro/Ala↓ . Internal cleavage of PrP C , a protein of >200 residues, is not in line with the canonical function of DPP4, but certain DPP4 inhibitors target FAP as well; indeed, the most effective compounds in our study, linagliptin and talabostat, reportedly inhibit FAP with IC 50 s of 370 nM and 70 nM, respectively, which are closer to the values we observed than the relatively consistent low-nanomolar potencies that the DPP4 inhibitors display toward DPP4 itself ( 34 , 35 ). Moreover, in addition to its DPP4-like exopeptidase activity, FAP acts as an endopeptidase favoring the sequence Gly–Pro↓ ( 30 , 36 , 37 )—motifs present in multiple copies within the mutated S3 PrP OR domain (Gly–Gly–Gly/Ser→Gly–Pro–Gly/Ser).…”
The cellular prion protein (PrP
C
) converts to alternatively folded pathogenic conformations (PrP
Sc
) in prion infections and binds neurotoxic oligomers formed by amyloid-β α-synuclein, and tau. β-Endoproteolysis, which splits PrP
C
into N- and C-terminal fragments (N2 and C2, respectively), is of interest because a protease-resistant, C2-sized fragment (C2
Sc
) accumulates in the brain during prion infections, seemingly comprising the majority of PrP
Sc
at disease endpoint in mice. However, candidates for the underlying proteolytic mechanism(s) remain unconfirmed in vivo. Here, a cell-based screen of protease inhibitors unexpectedly linked type II membrane proteins of the S9B serine peptidase subfamily to PrP
C
β-cleavage. Overexpression experiments in cells and assays with recombinant proteins confirmed that fibroblast activation protein (FAP) and its paralog, dipeptidyl peptidase-4 (DPP4), cleave directly at multiple sites within PrP
C
’s N-terminal domain. For wild-type mouse and human PrP
C
substrates expressed in cells, the rank orders of activity were human FAP ~ mouse FAP > mouse DPP4 > human DPP4 and human FAP > mouse FAP > mouse DPP4 >> human DPP4, respectively. C2 levels relative to total PrP
C
were reduced in several tissues from FAP-null mice, and, while knockout of DPP4 lacked an analogous effect, the combined DPP4/FAP inhibitor linagliptin, but not the FAP-specific inhibitor SP-13786, reduced C2
Sc
and total PrP
Sc
levels in two murine cell-based models of prion infections. Thus, the net activity of the S9B peptidases FAP and DPP4 and their cognate inhibitors/modulators affect the physiology and pathogenic potential of PrP
C
.
“…The different classes differ, however, in their distributions of mutational effects, with substitutions and insertions in the N-terminus more likely to impair rather than enhance aggregation but single and multi-AA deletions more likely to enhance rather than impair it. N-terminal truncations of Aβ are particularly likely to accelerate nucleation, raising the intriguing possibility that increased production of N-terminally truncated forms of Aβ triggered by environmental exposures, pathogens or genetics might be an important cause of familial and sporadic AD 50 . Fig.…”
Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms. To date, MAVEs have focussed on a single mutation type—amino acid (AA) substitutions—despite the diversity of coding variants that cause disease. Here we use Deep Indel Mutagenesis (DIM) to generate a comprehensive atlas of diverse variant effects for a disease protein, the amyloid beta (Aβ) peptide that aggregates in Alzheimer’s disease (AD) and is mutated in familial AD (fAD). The atlas identifies known fAD mutations and reveals that many variants beyond substitutions accelerate Aβ aggregation and are likely to be pathogenic. Truncations, substitutions, insertions, single- and internal multi-AA deletions differ in their propensity to enhance or impair aggregation, but likely pathogenic variants from all classes are highly enriched in the polar N-terminal region of Aβ. This comparative atlas highlights the importance of including diverse mutation types in MAVEs and provides important mechanistic insights into amyloid nucleation.
“…Antonyan et al [ 23 ] have demonstrated that purified DPP4 acts together with glutaminyl cyclase (QC) activity to generate Aβ pE3-40/42 in vitro by MALDI-TOF mass spectrometry. Valverde et al [ 26 ] added convincing evidence that human recombinant DPP4 is the rate-limiting enzyme liberating Aβ 3- X from its precursor Aβ 1- X : (i) Pharmacological treatment with a DPP4-specific inhibitor elevated levels of full-length Aβ on the expense of Aβ pE3-40 . (ii) Lentiviral expression of mutant APP cDNA in wild-type mouse brain and pharmacological blocking of DPP4 activity in brain in situ rescued dendritic spine morphology.…”
Section: Generation Of Pyroglutamate Aβmentioning
confidence: 99%
“…In addition, meprin-β can cut between Met-1 and Asp+2 independent from BACE1 [ 20 ]. DPP4 is responsible for the cleavage of the first two N-terminal amino acids of full-length Aβ 1- X generating Aβ 3- X [ 23 , 26 ]. There is one clinical study published that investigated the influence of DPP4 inhibition in patients with dementia [ 52 ].…”
One of the central aims in Alzheimer’s disease (AD) research is the identification of clinically relevant drug targets. A plethora of potential molecular targets work very well in preclinical model systems both in vitro and in vivo in AD mouse models. However, the lack of translation into clinical settings in the AD field is a challenging endeavor. Although it is long known that N-terminally truncated and pyroglutamate-modified Abeta (AβpE3) peptides are abundantly present in the brain of AD patients, form stable and soluble low-molecular weight oligomers, and induce neurodegeneration in AD mouse models, their potential as drug target has not been generally accepted in the past. This situation has dramatically changed with the report that passive immunization with donanemab, an AβpE3-specific antibody, cleared aymloid plaques and stabilized cognitive deficits in a group of patients with mild AD in a phase II trial. This review summarizes the current knowledge on the molecular mechanisms of generation of AβpE, its biochemical properties, and the intervention points as a drug target in AD.
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