Can dipeptidyl peptidase-4 inhibitors treat cognitive disorders?

Cheng, Qi; Cheng, Jinquan; Cordato, Dennis; Gao, Jianqun

doi:10.1016/j.pharmthera.2020.107559

Cited by 16 publications

(19 citation statements)

References 143 publications

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“…DPP4 inhibitors have been proposed as means to interfere with cognitive disorders ( 25 ). Most of studies deal with type 2 diabetes, a well-recognized risk factor for cognitive dysfunctions and dementia ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

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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

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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

Section: Discussionmentioning

confidence: 99%

“…Therefore, DPP4 appears as a good enzyme candidate responsible for the rate-limiting removal of this dipeptide. Indeed, few studies showed that DPP4 could, in concert with glutaminyl cyclase, yield pE3-40/42Aβ, in vitro (23) and that DPP4 inhibitors could prove useful as an AD treatment (24,25).…”

Section: Introductionmentioning

confidence: 99%

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

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show abstract

“…Not only clinical trials but also animal experiments indicate GLP‐1R agonists could improve neurodegenerative diseases, such as Parkinson's disease 13,14 and Alzheimer's disease, 15,16 while GLP‐1R also exerts therapeutic efficacy on brain ischemia, 17,18 traumatic brain injury, 19 and psychiatric disorders 20–22 in animal models. Besides, various kinds of DPP‐4 inhibitors, which can increase the level of endogenous GLP‐1 level, exhibit neuroprotective and cognitive protective effects either 23–25 …”

Section: Introductionmentioning

confidence: 99%

“…Besides, various kinds of DPP‐4 inhibitors, which can increase the level of endogenous GLP‐1 level, exhibit neuroprotective and cognitive protective effects either. 23 , 24 , 25 …”

Section: Introductionmentioning

confidence: 99%

Liraglutide attenuate central nervous inflammation and demyelination through AMPK and pyroptosis‐related NLRP3 pathway

et al. 2022

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Aims Multiple sclerosis (MS) still maintains increasing prevalence and poor prognosis, while glucagon‐like peptide‐1 receptor (GLP‐1R) agonists show excellent neuroprotective capacities recently. Thus, we aim to evaluate whether the GLP‐1R agonist liraglutide (Lira) could ameliorate central nervous system demyelination and inflammation. Methods The therapeutic effect of Lira was tested on experimental autoimmune encephalitis (EAE) in vivo and a microglia cell line BV2 in vitro. Results Lira administration could ameliorate the disease score of EAE mice, delay the disease onset, ameliorate pathological demyelination and inflammation score in lumbar spinal cord, reduce pathogenic T helper cell transcription in spleen, restore phosphorylated adenosine monophosphate‐activated protein kinase (pAMPK) level, autophagy level, and inhibit pyroptosis‐related NLR family, pyrin domain‐containing protein 3 (NLRP3) pathway in lumbar spinal cord. Additionally, cell viability test, lactate dehydrogenase release test, and dead/live cell staining test for BV2 cells showed Lira could not salvage BV2 from nigericin‐induced pyroptosis significantly. Conclusion Lira has anti‐inflammation and anti‐demyelination effect on EAE mice, and the protective effect of Lira in the EAE model may be related to regulation of pAMPK pathway, autophagy, and NLRP3 pathway. However, Lira treatment cannot significantly inhibit pyroptosis of BV2 cells in vitro. Our study provides Lira as a potential candidate for Multiple Sclerosis treatment.

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“…10 Consistently, DPP4 inhibitors, which are now widely used antidiabetic drugs in clinical practice, have been proven to ameliorate cognitive impairment in models of neurodegenerative and cerebrovascular diseases with multiple mechanisms likely to be involved including reduced oxidative stress and neuroinflammation and glucagon-like peptide-1 (GLP-1)-mediated decreases in amyloid beta (Aβ) plaque formation and tau phosphorylation. 11 Although increased DPP4 activity is implicated in the pathogenesis of cognitive impairment, findings supporting the association between DPP4 activity inhibitors and cognitive impairment in diabetic patients are inconsistent. In two studies, for example, treatments with DPP4 activity inhibitors have proven protective effects on cognitive function in elderly diabetic patients, 12,13 whereas another study with larger sample size reported that a DPP4 activity inhibitor (linagliptin) did not modulate cognitive decline in diabetic patients.…”

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confidence: 99%

Nonenzymatic function of DPP4 in diabetes‐associated mitochondrial dysfunction and cognitive impairment

Sun

Xiao

et al. 2021

Alzheimer's & Dementia

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Dipeptidyl peptidase-4 (DPP4) has been proven to exert its functions by both enzymatic and nonenzymatic pathways. The nonenzymatic function of DPP4 in diabetesassociated cognitive impairment remains unexplored. We determined DPP4 protein concentrations or its enzymatic activity in type 2 diabetic patients and db/db mice and tested the impact of the non-enzymatic function of DPP4 on mitochondrial dysfunction and cognitive impairment both in vivo and in vitro. The results show that increased DPP4 activity was an independent risk factor for incident mild cognitive impairment (MCI) in type 2 diabetic patients. In addition, DPP4 was highly expressed in the hippocampus of db/db mice and contributed to mitochondria dysfunction and cognitive impairment. Mechanistically, DPP4 might bind to PAR2 in the hippocampus and trigger GSK-3β activation, which downregulates peroxisome proliferator-activated receptor gamma coactivator 1 alpha expression and leads to mitochondria dysfunction, thereby promoting cognitive impairment in diabetes. Our findings indicate that the nonenzymatic function of DPP4 might promote mitochondrial dysfunction and cognitive impairment in diabetes.

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Can dipeptidyl peptidase-4 inhibitors treat cognitive disorders?

Cited by 16 publications

References 143 publications

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

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

Liraglutide attenuate central nervous inflammation and demyelination through AMPK and pyroptosis‐related NLRP3 pathway

Nonenzymatic function of DPP4 in diabetes‐associated mitochondrial dysfunction and cognitive impairment

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