Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat

William Watremez, Joshua Jackson, Bushra Almari, Samantha L. McLean, Ben Grayson, Joanna C. Neill, Nicolas Fischer, Ahmad Allouche, Violette Koziel, Thierry Pillot, Michael K. Harte

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Ao). These small soluble Ao, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. Objective: The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β 1-42 oligomers (Ao 1-42 ) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. Methods: Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Ao 1-42 (10 μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbuminpositive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). Results: Acute ICV administration of Ao 1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. Conclusion: Taken together the results suggest that acute administration of soluble low-n Ao may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.

Original languageEnglish
Pages (from-to)213-226
Number of pages14
JournalJournal of Alzheimer's Disease
Volume62
Issue number1
DOIs
Publication statusPublished - 6 Feb 2018
Externally publishedYes

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