Chronic sleep restriction promotes brain inflammation and synapse loss, and potentiates memory impairment induced by amyloid-beta oligomers in mice

Author(s)

Kincheski, Grasielle C. ; Valentim, Isabela S. ; Clarke, Julia R. ; Cozachenco, Danielle ; Castelo-Branco, Morgana T. L. ; Ramos-Lobo, Angela M. ; Rumjanek, Vivian M. B. D. ; Donato, Jr., Jose ; De Felice, Fernanda G. ; Ferreira, Sergio T.

• Document type: Journal article
• Source: BRAIN BEHAVIOR AND IMMUNITY; v. 64, p. 140-151, AUG 2017.
• Web of Science Citations: 31

Abstract

It is increasingly recognized that sleep disturbances and Alzheimer's disease (AD) share a bidirectional relationship. AD patients exhibit sleep problems and alterations in the regulation of circadian rhythms; conversely, poor quality of sleep increases the risk of development of AD. The aim of the current study was to determine whether chronic sleep restriction potentiates the brain impact of amyloid-beta oligomers (ABOs), toxins that build up in AD brains and are thought to underlie synapse damage and memory impairment. We further investigated whether alterations in levels of pro-inflammatory mediators could play a role in memory impairment in sleep-restricted mice. We found that a single intracerebroventricular (i.c.v.) infusion of A beta Os disturbed sleep pattern in mice. Conversely, chronically sleep-restricted mice exhibited higher brain expression of pro-inflammatory mediators, reductions in levels of pre- and post-synaptic marker proteins, and exhibited increased susceptibility to the impact of i.c.v. infusion of a sub-toxic dose of ABOs (1 pmol) on performance in the novel object recognition memory task. Sleep-restricted mice further exhibited an increase in brain TNF-alpha levels in response to A beta Os. Interestingly, memory impairment in sleep-restricted A beta O-infused mice was prevented by treatment with the TNF-alpha neutralizing monoclonal antibody, infliximab. Results substantiate the notion of a dual relationship between sleep and AD, whereby A beta Os disrupt sleep/wake patterns and chronic sleep restriction increases brain vulnerability to A beta Os, and point to a key role of brain inflammation in increased susceptibility to A beta Os in sleep-restricted mice. (C) 2017 Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 14/50140-6 - Clams comprehensive Lab animal monitoring system
• Grantee: Jose Donato Junior
• Support Opportunities: Multi-user Equipment Program