Liraglutide Has Anti-Inflammatory and Anti-Amyloid Properties in Streptozotocin-Induced and 5xFAD Mouse Models of Alzheimer's Disease.

Leela Paladugu,Gary L Dunbar,Abeer Gharaibeh,Lixin Li,Tia C Hall,Cameron Learman,Nivya Kolli,Panchanan Maiti,Julien Rossignol

doi:10.3390/ijms22020860

Abstract

Recent clinical and epidemiological studies support the contention that diabetes mellitus (DM) is a strong risk factor for the development of Alzheimer’s disease (AD). The use of insulin cell toxin, streptozotocin (STZ), when injected into the lateral ventricles, develops an insulin resistant brain state (IRBS) and represents a non-transgenic, or sporadic AD model (SAD), with several AD-like neuropathological features. The present study explored the effects of an anti-diabetic drug, liraglutide (LIR), in reversing major pathological hallmarks in the prodromal disease stage of both the 5xFAD transgenic and SAD mouse models of AD. Three-month-old 5xFAD and age-matched wild type mice were given a single intracerebroventricular (i.c.v) injection of STZ or vehicle (saline) and were subsequently treated with LIR, intraperitoneally (IP), once a day for 30 days. The extent of neurodegeneration, Aβ plaque load, and key proteins associated with the insulin signaling pathways were measured using Western blot and neuroinflammation (via immunohistological assays) in the cortical and hippocampal regions of the brain were assessed following a series of behavioral tests used to measure cognitive function after LIR or vehicle treatments. Our results indicated that STZ significantly increased neuroinflammation, Aβ plaque deposition and disrupted insulin signaling pathway, while 25 nmol/kg LIR, when injected IP, significantly decreased neuroinflammatory responses in both SAD and 5xFAD mice before significant cognitive changes were observed, suggesting LIR can reduce early neuropathology markers prior to the emergence of overt memory deficits. Our results indicate that LIR has neuroprotective effects and has the potential to serve as an anti-inflammatory and anti-amyloid prophylactic therapy in the prodromal stages of AD.

Highlights

This article is an open access articleAlzheimer’s disease (AD) is the most common, progressive, age-related neurological disorder
Studies have been done to check the prophylactic effects of long-term administration of LIR in two-month-old double transgenic mice [23], to the best of our knowledge, this is the first study to assess the neuroprotective effects of LIR in the brains of both sporadic and transgenic 5xFAD mouse models that mimic the prodromal stage of the AD
Our results provide in vivo evidence that the initial stages of impaired insulin signaling, especially in 5xFAD mice brain can cause increased Aβ protein levels through the activity of Insulin-Degrading Enzyme (IDE), along with increased inflammatory response, to a greater extent in sporadic AD model (SAD)

Summary

Introduction

This article is an open access articleAlzheimer’s disease (AD) is the most common, progressive, age-related neurological disorder. The hallmark pathology of this disease is the accumulation of amyloid beta (Aβ) proteins in the form of intraneuronal inclusions and extracellular neuritic plaques, intracellular distributed under the terms and conditions of the Creative Commons. All the above-mentioned changes are prominent in the cortical and hippocampal regions of the brain [2,3,4]. Both genetic and environmental factors contribute to the pathogenesis of AD. A small percentage of cases of AD are associated with genetic factors, in the form of autosomal dominant inheritance of the genes producing amyloid precursor protein (APP), presenilin 1(PSEN1), and presenilin

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