Neuroprotective Effects of Dipeptidyl Peptidase 4 Inhibitor on Alzheimer's Disease: a Narrative Review

Overview

Journal Front Pharmacol

Date 2024 Feb 26

PMID 38405664

Authors

Xin Jiang

Ji Li

Xiaohui Yao

Hao Ding

Aihong Gu

Zhen Zhou

Affiliations

Soon will be listed here.

Abstract

Insulin resistance in brain and amyloidogenesis are principal pathological features of diabetes-related cognitive decline and development of Alzheimer's disease (AD). A growing body of evidence suggests that maintaining glucose under control in diabetic patients is beneficial for preventing AD development. Dipeptidyl peptidase 4 inhibitors (DDP4is) are a class of novel glucose-lowering medications through increasing insulin excretion and decreasing glucagon levels that have shown neuroprotective potential in recent studies. This review consolidates extant evidence from earlier and new studies investigating the association between DPP4i use, AD, and other cognitive outcomes. Beyond DPP4i's benefits in alleviating insulin resistance and glucose-lowering, underlying mechanisms for the potential neuroprotection with DPP4i medications were categorized into the following sections: (Ferrari et al., Physiol Rev, 2021, 101, 1,047-1,081): the benefits of DPP4is on directly ameliorating the burden of β-amyloid plaques and reducing the formation of neurofibrillary tangles; DPP4i increasing the bioactivity of neuroprotective DPP4 substrates including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and stromal-derived factor-1α (SDF-1α) etc.; pleiotropic effects of DPP4is on neuronal cells and intracerebral structure including anti-inflammation, anti-oxidation, and anti-apoptosis. We further revisited recently published epidemiological studies that provided supportive data to compliment preclinical evidence. Given that there remains a lack of completed randomized trials that aim at assessing the effect of DPP4is in preventing AD development and progression, this review is expected to provide a useful insight into DPP4 inhibition as a potential therapeutic target for AD prevention and treatment. The evidence is helpful for informing the rationales of future clinical research and guiding evidence-based clinical practice.

Citing Articles

In Vivo and Computational Studies on Sitagliptin's Neuroprotective Role in Type 2 Diabetes Mellitus: Implications for Alzheimer's Disease.

Mani V, Arfeen M Brain Sci. 2025; 14(12.

PMID: 39766390 PMC: 11674309. DOI: 10.3390/brainsci14121191.

References

Biessels G, Verhagen C, Janssen J, van den Berg E, Zinman B, Rosenstock J . Effect of Linagliptin on Cognitive Performance in Patients With Type 2 Diabetes and Cardiorenal Comorbidities: The CARMELINA Randomized Trial. Diabetes Care. 2019; 42(10):1930-1938. DOI: 10.2337/dc19-0783. View

Yuan L, Zhang J, Guo J, Holscher C, Yang J, Wu M . DAla2-GIP-GLU-PAL Protects Against Cognitive Deficits and Pathology in APP/PS1 Mice by Inhibiting Neuroinflammation and Upregulating cAMP/PKA/CREB Signaling Pathways. J Alzheimers Dis. 2021; 80(2):695-713. DOI: 10.3233/JAD-201262. View

Pelle M, Zaffina I, Giofre F, Pujia R, Arturi F . Potential Role of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Cognitive Decline and Dementia in Diabetes Mellitus. Int J Mol Sci. 2023; 24(14). PMC: 10379573. DOI: 10.3390/ijms241411301. View

Holscher C . Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases. J Endocrinol. 2013; 221(1):T31-41. DOI: 10.1530/JOE-13-0221. View

Waqas K, Muller M, Koedam M, El Kadi Y, Zillikens M, van der Eerden B . Methylglyoxal - an advanced glycation end products (AGEs) precursor - Inhibits differentiation of human MSC-derived osteoblasts in vitro independently of receptor for AGEs (RAGE). Bone. 2022; 164:116526. DOI: 10.1016/j.bone.2022.116526. View

Ussher J, Drucker D . Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nat Rev Cardiol. 2023; 20(7):463-474. DOI: 10.1038/s41569-023-00849-3. View

Zhang D, Shi N, Fang H, Ma L, Wu W, Zhang Y . Vildagliptin, a DPP4 inhibitor, alleviates diabetes-associated cognitive deficits by decreasing the levels of apoptosis-related proteins in the rat hippocampus. Exp Ther Med. 2018; 15(6):5100-5106. PMC: 5952083. DOI: 10.3892/etm.2018.6016. View

Chami B, Steel A, de la Monte S, Sutherland G . The rise and fall of insulin signaling in Alzheimer's disease. Metab Brain Dis. 2016; 31(3):497-515. DOI: 10.1007/s11011-016-9806-1. View

Salas I, Weerasekera A, Ahmed T, Callaerts-Vegh Z, Himmelreich U, DHooge R . High fat diet treatment impairs hippocampal long-term potentiation without alterations of the core neuropathological features of Alzheimer disease. Neurobiol Dis. 2018; 113:82-96. DOI: 10.1016/j.nbd.2018.02.001. View

10.

Gabbouj S, Ryhanen S, Marttinen M, Wittrahm R, Takalo M, Kemppainen S . Altered Insulin Signaling in Alzheimer's Disease Brain - Special Emphasis on PI3K-Akt Pathway. Front Neurosci. 2019; 13:629. PMC: 6591470. DOI: 10.3389/fnins.2019.00629. View

11.

Hung Y, Wang Y, Lee S . DPP-4 inhibitor reduces striatal microglial deramification after sensorimotor cortex injury induced by external force impact. FASEB J. 2020; 34(5):6950-6964. DOI: 10.1096/fj.201902818R. View

12.

Rohrborn D, Eckel J, Sell H . Shedding of dipeptidyl peptidase 4 is mediated by metalloproteases and up-regulated by hypoxia in human adipocytes and smooth muscle cells. FEBS Lett. 2014; 588(21):3870-7. DOI: 10.1016/j.febslet.2014.08.029. View

13.

Cassis P, Locatelli M, Cerullo D, Corna D, Buelli S, Zanchi C . SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy. JCI Insight. 2018; 3(15). PMC: 6129124. DOI: 10.1172/jci.insight.98720. View

14.

Kim Y, Jeon J, Kim H, Kim D, Lee K, Moon S . Risk of Dementia in Older Patients with Type 2 Diabetes on Dipeptidyl-Peptidase IV Inhibitors Versus Sulfonylureas: A Real-World Population-Based Cohort Study. J Clin Med. 2019; 8(1). PMC: 6352270. DOI: 10.3390/jcm8010028. View

15.

Kroller-Schon S, Knorr M, Hausding M, Oelze M, Schuff A, Schell R . Glucose-independent improvement of vascular dysfunction in experimental sepsis by dipeptidyl-peptidase 4 inhibition. Cardiovasc Res. 2012; 96(1):140-9. DOI: 10.1093/cvr/cvs246. View

16.

Sakr H . Effect of sitagliptin on the working memory and reference memory in type 2 diabetic Sprague-Dawley rats: possible role of adiponectin receptors 1. J Physiol Pharmacol. 2013; 64(5):613-23. View

17.

Kornelius E, Lin C, Chang H, Li H, Huang W, Yang Y . DPP-4 Inhibitor Linagliptin Attenuates Aβ-induced Cytotoxicity through Activation of AMPK in Neuronal Cells. CNS Neurosci Ther. 2015; 21(7):549-57. PMC: 5033019. DOI: 10.1111/cns.12404. View

18.

Sanfilippo C, Castrogiovanni P, Imbesi R, Nunnari G, Di Rosa M . Postsynaptic damage and microglial activation in AD patients could be linked CXCR4/CXCL12 expression levels. Brain Res. 2020; 1749:147127. DOI: 10.1016/j.brainres.2020.147127. View

19.

Wicinski M, Wodkiewicz E, Slupski M, Walczak M, Socha M, Malinowski B . Neuroprotective Activity of Sitagliptin via Reduction of Neuroinflammation beyond the Incretin Effect: Focus on Alzheimer's Disease. Biomed Res Int. 2018; 2018:6091014. PMC: 6116461. DOI: 10.1155/2018/6091014. View

20.

Borzi A, Condorelli G, Biondi A, Basile F, Vicari E, Buscemi C . Effects of vildagliptin, a DPP-4 inhibitor, in elderly diabetic patients with mild cognitive impairment. Arch Gerontol Geriatr. 2019; 84:103896. DOI: 10.1016/j.archger.2019.06.001. View