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Neuropharmacology. 2019 Jun 12;157:107668. doi: 10.1016/j.neuropharm.2019.107668. [Epub ahead of print]

DPP-4 inhibitor improves learning and memory deficits and AD-like neurodegeneration by modulating the GLP-1 signaling.

Author information

1
Pathophysiology Department, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
2
Department of Pathology, Tianjin People's Hospital, Tianjin, China.
3
Department of Pathology, Tianjin Tumor Hospital, Tianjin Medical University, Tianjin, China.
4
Pathophysiology Department, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. Electronic address: dengyq@tmu.edu.cn.

Abstract

Glucagon-like peptide-1 (GLP-1) signaling in the brain plays an important role in the regulation of glucose metabolism, which is impaired in Alzheimer's disease (AD). Here, we detected the GLP-1 and GLP-1 receptor (GLP-1R) in AD human brain and APP/PS1/Tau transgenic (3xTg) mice brain, finding that they were both decreased in AD human and mice brain. Enhanced GLP-1 exerts its protective effects on AD, however, this is rapidly degraded into inactivated metabolites by dipeptidyl peptidase-4 (DPP-4), resulting in its extremely short half-time. DPP-4 inhibitors, thus, was applied to improve the level of GLP-1 and GLP-1R expression in the hippocampus and cortex of AD mice brains. It is also protected learning and memory and synaptic proteins, increased the O-Glycosylation and decreased abnormal phosphorylation of tau and neurofilaments (NFs), degraded intercellular β-amyloid (Aβ) accumulation and alleviated neurodegeneration related to GLP-1 signaling pathway.

KEYWORDS:

Alzheimer's disease; Dipeptidyl peptidase-4 inhibitor;; GLP-1 signaling; NFs; Neurodegeneration; Tau

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