Chronic treatment with the α2-adrenoceptor antagonist fluparoxan prevents age-related deficits in spatial working memory in APP×PS1 transgenic mice without altering β-amyloid plaque load or astrocytosis.

Abstract

Locus coeruleus degeneration and reduced central noradrenaline content is an early feature of Alzheimer's disease. In transgenic mouse models of Alzheimer's disease-like pathology, lesioning the locus coeruleus exacerbates β-amyloid (Aβ) pathology, neuroinflammation and memory deficits. Here we aimed to determine whether chronic treatment with the α(2)-adrenoceptor antagonist fluparoxan, that enhances noradrenaline release, can prevent the onset of Alzheimer's-like pathology and memory deficits in APP/PS1 transgenic mice (TASTPM). Fluparoxan (1mg/kg/day) was administered to TASTPM and wild type mice from 4 to 8 months of age. Memory was assessed at 4 and 8 months of age using the Morris water maze and contextual fear conditioning and at monthly intervals during the duration of treatment using the object recognition and spontaneous alternation task. Aβ plaque load and astrocytosis were measured at 4 and 8 months of age by immunohistochemistry. Fluparoxan treatment prevented age-related spatial working memory deficits in the spontaneous alternation task but not spatial reference memory deficits in the Morris water maze. Aβ plaque load and astrocytosis were unaltered by fluparoxan treatment in TASTPM mice. The findings suggest that fluparoxan treatment selectively prevent the decline of forms of memory where noradrenaline plays an integral role and that this beneficial effect is not due to altered Aβ plaque pathology or astrocytosis.

• Authors: G A Scullion, D A Kendall, C A Marsden, D Sunter, M-C Pardon
• Journal: Neuropharmacology (Neuropharmacology) 2011 Feb-Mar Vol. 60 Issue 2-3 Pg. 223-34 ISSN: 1873-7064 [Electronic] England
• PMID: 20850464 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Adrenergic alpha-2 Receptor Antagonists
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Presenilin-1
• Pyrroles
• Receptors, Adrenergic, alpha-2
• Piperoxan
• fluparoxan

Topics

• Adrenergic alpha-2 Receptor Antagonists (administration & dosage)
• Aging (genetics, metabolism, pathology)
• Amyloid beta-Peptides (biosynthesis, genetics)
• Amyloid beta-Protein Precursor (biosynthesis, genetics)
• Animals
• Astrocytes (drug effects, metabolism, pathology)
• Gliosis (drug therapy, genetics, metabolism)
• Humans
• Longitudinal Studies
• Memory Disorders (genetics, metabolism, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Piperoxan (administration & dosage, analogs & derivatives)
• Plaque, Amyloid (drug therapy, genetics, metabolism)
• Presenilin-1 (biosynthesis, genetics)
• Pyrroles (administration & dosage)
• Receptors, Adrenergic, alpha-2 (physiology)
• Treatment Outcome