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The many facets of CD26/dipeptidyl peptidase 4 and its inhibitors in disorders of the CNS – a critical overview

  • Hans-Gert Bernstein EMAIL logo , Gerburg Keilhoff , Henrik Dobrowolny and Johann Steiner
Published/Copyright: July 1, 2022
Become an author with De Gruyter Brill

Abstract

Dipeptidyl peptidase 4 is a serine protease that cleaves X-proline or X-alanine in the penultimate position. Natural substrates of the enzyme are glucagon-like peptide-1, glucagon inhibiting peptide, glucagon, neuropeptide Y, secretin, substance P, pituitary adenylate cyclase-activating polypeptide, endorphins, endomorphins, brain natriuretic peptide, beta-melanocyte stimulating hormone and amyloid peptides as well as some cytokines and chemokines. The enzyme is involved in the maintenance of blood glucose homeostasis and regulation of the immune system. It is expressed in many organs including the brain. DPP4 activity may be effectively depressed by DPP4 inhibitors. Apart from enzyme activity, DPP4 acts as a cell surface (co)receptor, associates with adeosine deaminase, interacts with extracellular matrix, and controls cell migration and differentiation. This review aims at revealing the impact of DPP4 and DPP4 inhibitors for several brain diseases (virus infections affecting the brain, tumours of the CNS, neurological and psychiatric disorders). Special emphasis is given to a possible involvement of DPP4 expressed in the brain.While prominent contributions of extracerebral DPP4 are evident for a majority of diseases discussed herein; a possible role of “brain” DPP4 is restricted to brain cancers and Alzheimer disease. For a number of diseases (Covid-19 infection, type 2 diabetes, Alzheimer disease, vascular dementia, Parkinson disease, Huntington disease, multiple sclerosis, stroke, and epilepsy), use of DPP4 inhibitors has been shown to have a disease-mitigating effect. However, these beneficial effects should mostly be attributed to the depression of “peripheral” DPP4, since currently used DPP4 inhibitors are not able to pass through the intact blood–brain barrier.


Corresponding author: Hans-Gert Bernstein, Department of Psychiatry and Psychotherapy, Otto v. Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany, E-mail:

  1. Author contributions: H.-G. B. designed the concept and wrote the paper; G.K. contributed to the discussion and writing; H.D. contributed to the review of literature and to the discussion; J.S. contributed to the writing and editing of the manuscript.

  2. Research funding: None declared.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

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Received: 2022-03-10
Accepted: 2022-05-10
Published Online: 2022-07-01
Published in Print: 2023-01-27

© 2022 Walter de Gruyter GmbH, Berlin/Boston

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