Abstract
Alzheimer's disease (AD), the most common form of dementia in the older people, is a multifactoral pathology, characterized by cognitive deficits, increase in cerebral deposition of the β-amyloid (Aβ) peptide, neurofibrillary tangles, and neurodegeneration. Studies currently support a central role of neuroinflammation, through production of proinflammatory cytokines including excess tumor necrosis factor α (TNF-α) in the pathogenesis of AD, especially in Aβ-induced cognitive deficits. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and neuroprotective effects. This study investigates the effect of imipramine on alterations of long-term and short-term memories, TNF-α expression, and amyloid precursor protein (APP) processing induced by intracerebroventricular injection of Aβ25-35 in mice. Mice were treated with imipramine (10 mg/kg i.p. once a day for 13 days) from the day after the Aβ25-35 injection. Memory function was evaluated in the water-maze (days 10–14) and Y-maze (day 9) tests. TNF-α levels and APP processing were examined in the frontal cortex and the hippocampus (day 14). Imipramine significantly prevented memory deficits caused by Aβ25-35 in the water-maze and Y-maze tests, and inhibited the TNF-α increase in the frontal cortex. Moreover, imipramine decreased the elevated levels of Aβ both in frontal cortex and hippocampus with different modulations of APP and C-terminal fragments of APP. So, imipramine prevents memory impairment through its intrinsic property to inhibit TNF-α and Aβ accumulation and may represent a potential candidate for AD treatment.
Footnotes
This work was supported by the French Ministry of Education and Research [Grant 2008 1222] (to Research Unit GREVIC, EA 3808, University of Poitiers and University Hospital of Poitiers).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.162164
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ABBREVIATIONS:
- Aβ
- β-amyloid peptide
- AD
- Alzheimer's disease
- APP
- amyloid precursor protein
- BACE
- β-APP-converting enzyme
- BBB
- blood-brain barrier
- CNS
- central nervous system
- CTF
- C-terminal fragment of APP
- i.c.v.
- intracerebroventricularly
- RT
- room temperature
- TNF-α
- tumor necrosis factor α
- TNFR1
- tumor necrosis factor receptor 1
- TBST
- Tris-buffered saline Tween 20
- ANOVA
- analysis of variance
- ELISA
- enzyme-linked immunosorbent assay
- PBS
- phosphate-buffered saline
- UHQ
- ultrahigh quality.
- Received September 29, 2009.
- Accepted November 3, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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