A GLP-1/GIP dual receptor agonist DA4-JC effectively attenuates cognitive impairment and pathology in the APP/PS1/Tau model of Alzheimer’s disease

Bibliographic

Year of Publication:

2021

Contact PI Name:

Christian Holscher

Contact PI Affiliation:

Neuroscience Research Group, Henan University of Chinese Medicine, Zhengzhou, China

Co-Authors:

Hong-Yan Cai, Dan Yanga, Jing Qiao, Jun-Ting Yang, Zhao-Jun Wang, Mei-Na Wu, Jin-Shun Q

Primary Reference (PubMED ID):

34366339

Funding Source:

National Natural Science Foundation of China

Ministry of Education of China

Fund for Shanxi 1331 Project Key Subjects Construction

Key Laboratory of Cellular Physiology of Shanxi Medical University

Shanxi Scholarship Council of China

Study Goal and Principal Findings:

Background: Alzheimer's disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs.

Objective: To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD.

Methods: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers.

Results: DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels.

Conclusion: DA4-JC is a promising drug for the treatment of AD.

Bibliographic Notes:

Hong-Yan Cai (Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, China) and Christian Holscher (Neuroscience Research Group, Henan University of Chinese Medicine, Zhengzhou, China) are corresponding authors on this paper.

Therapeutic Agent

Therapeutic Information:

Therapy Type:

Biologic - Peptide

Therapeutic Agent:

DA4-JC

PubMed

Patents

Therapeutic Target:

Glucagon-Like Peptide 1 Receptor (GLP-1R)

Open Targets

Pharos

Agora

Therapeutic Target:

Glucose-Dependent Insulinotropic Polypeptide (GIP) Receptor

Open Targets

Pharos

Agora

Animal Model

Model Information:

Species:

Mouse

Model Type:

APPxPS1xTau

Model Name:

3xTg

ALZFORUM

Strain/Genetic Background:

Not Reported

Species:

Mouse

Model Type:

Non-transgenic

Model Name:

C57BL/6

Strain/Genetic Background:

C57BL/6J

Experimental Design

Is the following information reported in the study?:

Power/Sample Size Calculation

Randomized into Groups

Blinded for Treatment

Blinded for Outcome Measures

Pharmacokinetic Measures

Pharmacodynamic Measures

Toxicology Measures

ADME Measures

Biomarkers

Dose

Formulation

Route of Delivery

Duration of Treatment

Frequency of Administration

Age of Animal at the Beginning of Treatment

Age of Animal at the End of Treatment

Sex as a Biological Variable

Study Balanced for Sex as a Biological Variable

Number of Premature Deaths

Number of Excluded Animals

Statistical Plan

Genetic Background

Inclusion/Exclusion Criteria Included

Conflict of Interest

Outcomes

Outcome Measured

Outcome Parameters

Behavioral

Contextual Fear Conditioning

Exploratory Activity

Morris Water Maze

Novel Object Recognition Test (NORT)

Open Field Test

Spontaneous Alternation

Y Maze

Motor Function

Locomotor Activity

Path Length

Swimming Speed

Histopathology

beta Amyloid Deposits

phospho-Tau

Synaptic Loss

Biochemical

p62/Sequestosome 1 (SQSTM1)

Parkin

Postsynaptic Density Protein 95 (PSD95)

PTEN Induced Kinase 1 (PINK1)

Synaptophysin

Immunochemistry

Brain-beta Amyloid Deposits

phospho-Tau

Microscopy

Dendritic Spine Number

Dendritic Spine Density

Electron Microscopy

Mitochondria Count

Mitochondria Morphology

Synaptic Density

Spectroscopy

Matrix-Assisted Laser Desorption/Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry

Electrophysiology

field Excitatory Postsynaptic Potential (fEPSP)

Input/Output (I/O) Curve

Long Term Potentiation (LTP)

Paired-Pulse Facilitation (PPF)

Toxicology

Body Weight