Dipeptidyl peptidase 4 contributes to Alzheimer’s disease–like defects in a mouse model and is increased in sporadic Alzheimer’s disease brains
| Autor: | Audrey Valverde, Julie Dunys, Thomas Lorivel, Delphine Debayle, Anne-Sophie Gay, Céline Caillava, Mounia Chami, Frédéric Checler |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
dendrites morphology
Plaque Amyloid Peptide Biochemistry EBSS Earles’ Balanced Salt solution Mice chemistry.chemical_compound pE3-Aβ Amyloid precursor protein E3-Aβ Glu3-Aβ Senile plaques senile plaques Peptide sequence chemistry.chemical_classification APPwt wild-type APP biology flAβ full-length Aβ Brain Aβ load Cell biology APPswe APP bearing the Swedish mutation Research Article pE3-Aβ pyroGlu3–Aβ Aβ amyloid β APA aminopeptidase A Dipeptidyl Peptidase 4 Transgene shDPP4 shRNA probes targeting DPP4 AD Alzheimer’s disease APP amyloid precursor protein Alzheimer Disease mental disorders 3xTg-AD triple transgenic AD Animals Humans DAPI QC glutaminyl cyclase Molecular Biology Dipeptidyl peptidase-4 shScr shRNA corresponding to a control scramble sequence behavior DPP4 dipeptidyl aminopeptidase 4 Cell Biology 3xTg-AD Disease Models Animal MWM Morris water maze Enzyme chemistry biology.protein FCS fetal calf serum DAPI 4′ 6-diamidino-2-phenylindole |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | The amyloid cascade hypothesis, which proposes a prominent role for full-length amyloid β peptides in Alzheimer's disease, is currently being questioned. In addition to full-length amyloid β peptide, several N-terminally truncated fragments of amyloid β peptide could well contribute to Alzheimer's disease setting and/or progression. Among them, pyroGlu3-amyloid β peptide appears to be one of the main components of early anatomical lesions in Alzheimer's disease-affected brains. Little is known about the proteolytic activities that could account for the N-terminal truncations of full-length amyloid β, but they appear as the rate-limiting enzymes yielding the Glu3-amyloid β peptide sequence that undergoes subsequent cyclization by glutaminyl cyclase, thereby yielding pyroGlu3-amyloid β. Here, we investigated the contribution of dipeptidyl peptidase 4 in Glu3-amyloid β peptide formation and the functional influence of its genetic depletion or pharmacological blockade on spine maturation as well as on pyroGlu3-amyloid β peptide and amyloid β 42-positive plaques and amyloid β 42 load in the triple transgenic Alzheimer's disease mouse model. Furthermore, we examined whether reduction of dipeptidyl peptidase 4 could rescue learning and memory deficits displayed by these mice. Our data establish that dipeptidyl peptidase 4 reduction alleviates anatomical, biochemical, and behavioral Alzheimer's disease-related defects. Furthermore, we demonstrate that dipeptidyl peptidase 4 activity is increased early in sporadic Alzheimer's disease brains. Thus, our data demonstrate that dipeptidyl peptidase 4 participates in pyroGlu3-amyloid β peptide formation and that targeting this peptidase could be considered as an alternative strategy to interfere with Alzheimer's disease progression. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|