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Research Paper|Volume 12, Issue 6|pp 5469—5478

Intranasal delivery of 9-cis retinoic acid reduces beta-amyloid deposition via inhibiting astrocyte-mediated inflammation

Hong Zhao1, Shuo Li2, Zhuo Li3, Shuo Yang1, Dandan Li4, Jiaolin Zheng5, Hongmei Gao1, Ling Yun1, YingLi Gu1, Longxuan Li6, Jing Zhao7, Yuan Fu1
  • 1Department of Neurology, The Fourth Hospital of Harbin Medical University, Harbin, China
  • 2Department of Ultrasonography, The Fourth Hospital of Harbin Medical University, Harbin, China
  • 3Department of Endocrinology, The First Hospital of Jilin University, Changchun, China
  • 4Department of Neurology, The Second Hospital of Heilongjiang Province, Harbin, China
  • 5Department of Neurology, The Second Hospital of Harbin Medical University, Harbin, China
  • 6Department of Neurology, Gongli Hospital of The Second Military Medical University, Shanghai, China
  • 7Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
* Co-first authors
Received: November 9, 2019Accepted: January 27, 2020Published: March 25, 2020
https://doi.org/10.18632/aging.102970

Copyright © 2020 Zhao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Alzheimer's disease (AD) is associated with the accumulation and deposition of a beta-amyloid (Αβ) peptide in the brain, resulting in increased neuroinflammation and synaptic dysfunction. Intranasal delivery of targeted drugs to the brain represents a noninvasive pathway that bypasses the blood-brain barrier and minimizes systemic exposure. The aim of this study was to evaluate the therapeutic effect of intranasally delivered 9-cis retinoic acid (RA) on the neuropathology of an AD mouse model. Herein, we observed dramatically decreased Αβ deposition in the brains of amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice (APP/PS1) treated intranasally with 9-cis RA for 4 weeks compared to that in the brains of vehicle-treated mice. Importantly, intranasal delivery of 9-cis RA suppressed Αβ-associated astrocyte activation and neuroinflammation and ultimately restored synaptic deficits in APP/PS1 transgenic mice. These results support the critical roles of Αβ-associated neuroinflammation responses to synaptic deficits, particularly during the deposition of Αβ. Our findings provide strong evidence that intranasally delivered 9-cis RA attenuates neuronal dysfunction in an AD mouse model and is a promising therapeutic strategy for the prevention and treatment of AD.