Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer's disease.

Abstract

Neuroinflammation is a pervasive feature of Alzheimer's disease (AD) and characterized by activated microglia, increased proinflammatory cytokines and/or infiltrating immune cells. T helper 17 (Th17) cells are found in AD brain parenchyma and interleukin-17A (IL-17A) is identified around deposits of aggregated amyloid β protein (Aβ). However, the role of IL-17A in AD pathogenesis remains elusive. We overexpressed IL-17A in an AD mouse model via recombinant adeno-associated virus serotype 5 (rAAV5)-mediated intracranial gene delivery. AD model mice subjected to injection of a vehicle (PBS) or rAAV5 carrying the lacZ gene served as controls. IL-17A did not exacerbate neuroinflammation in IL-17A-overexpressing mice. We found that IL-17A overexpression markedly improved glucose metabolism, decreased soluble Aβ levels in the hippocampus and cerebrospinal fluid, drastically reduced cerebral amyloid angiopathy, and modestly but significantly improved anxiety and learning deficits. Moreover, the ATP-binding cassette subfamily A member 1 (ABCA1), which can transport Aβ from the brain into the blood circulation, significantly increased in IL-17A-overexpressing mice. In vitro treatment of brain endothelial bEnd.3 cells with IL-17A induced a dose-dependent increase in protein expression of ABCA1 through ERK activation. Our study suggests that IL-17A may decrease Aβ levels in the brain by upregulating ABCA1 in blood-brain barrier endothelial cells.

• Authors: Junling Yang, Jinghong Kou, Robert Lalonde, Ken-Ichiro Fukuchi
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 65 Pg. 262-273 (Oct 2017) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 28526436 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter 1
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Cytokines
• Interleukin-17

Topics

• ATP Binding Cassette Transporter 1 (genetics, metabolism)
• Alzheimer Disease (genetics, metabolism)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Blood-Brain Barrier (metabolism)
• Brain (metabolism)
• Cerebral Amyloid Angiopathy (genetics, metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Hippocampus (metabolism)
• Interleukin-17 (genetics, metabolism, pharmacology)
• Mice
• Mice, Inbred DBA
• Microglia (metabolism)
• Th17 Cells (metabolism)
• Transcriptional Activation
• Up-Regulation