Aging exacerbates cognitive and anxiety alterations induced by an intracerebroventricular injection of amyloid-β1-42 peptide in mice.

Abstract

An increasing body of evidence indicates that the activation of indoleamine-2,3-dyoxigenase (IDO), a first and rate-limiting enzyme in the kynurenine (KYN) pathway, is involved in Aβ1-42-neurotoxicity and AD pathogenesis. We have reported for the first time that brain IDO activation is related to Aβ1-42 exposure in young mice. Because aging is characterized by a brain dyshomeostasis and because it remains the most dominant risk factor for AD, the purpose of this study was to determine whether aging is associated with a higher sensitivity to behavioural and neurochemical alterations elicited by an intracerebroventricular (i.c.v.) injection of Aβ1-42 (400 pmol/mice), and whether KYN pathway is involved in these effects. We confirmed that aged mice displayed higher cognitive deficit in the object recognition test and higher anxiety-like behaviour in the elevated plus-maze and open field tests after the Aβ1-42 administration. Aged mice also responded to Aβ1-42 with a higher deficiency of brain-derived neurotrophic factor, glutathione levels and total radical-trapping antioxidant capacity, a higher IDO activity, and a higher KYN and KYN/tryptophan ratio in the prefrontal cortex and hippocampus. These effects of Aβ1-42 were associated with a higher proinflammatory status, as measured by higher levels of interleukin-6, lower levels of interleukin-10 and higher expression of glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (Iba1) in the brain of aged mice. These results represent primary evidence suggesting that age-associated inflammatory signature and down-regulation of neuroprotectants in the brain render aged mice more vulnerable to Aβ1-42-induced memory loss, anxiety symptoms and KYN pathway dysregulation.

• Authors: Leandro Cattelan Souza, Cristiano R Jesse, Lucian Del Fabbro, Marcelo Gomes de Gomes, Nathalie Savedra Gomes, Carlos Borges Filho, André Tiago Rossito Goes, Ethel Antunes Wilhelm, Cristiane Luchese, Silvane Souza Roman, Silvana Peterini Boeira
• Journal: Molecular and cellular neurosciences (Mol Cell Neurosci) Vol. 88 Pg. 93-106 (04 2018) ISSN: 1095-9327 [Electronic] United States
• PMID: 29369791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Brain-Derived Neurotrophic Factor
• Glial Fibrillary Acidic Protein
• Neuroprotective Agents
• Peptide Fragments

Topics

• Aging (physiology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Anxiety (physiopathology)
• Brain-Derived Neurotrophic Factor (metabolism)
• Cognition (physiology)
• Disease Models, Animal
• Glial Fibrillary Acidic Protein (metabolism)
• Hippocampus (metabolism)
• Male
• Memory Disorders (physiopathology)
• Mice
• Neuroprotective Agents (pharmacology)
• Peptide Fragments (metabolism)
• Prefrontal Cortex (metabolism)