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Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
Chronic administration of Dimebon does not ameliorate amyloid-β pathology in 5xFAD transgenic mice
Owen M Peters1, Tatyana Shelkovnikova, Tatiana Tarasova
1School of Biosciences, Cardiff University, Museum Avenue, Cardiff, United Kingdom.
Abstract:
Dimebon has been tested as a potential modifier of Alzheimer's disease (AD), resulting in mixed clinical trial outcomes. Originally utilized as an antihistamine, Dimebon was later found to ameliorate AD symptoms in initial human trials. Although subsequent trials have reportedly failed to replicate these finding, there is a growing body of evidence that Dimebon might be neuroprotective in certain models of neurodegeneration. The precise mechanism by which Dimebon is thought to act in AD is unclear, though changes in receptor activity, mitochondria function, and autophagy activity have been proposed. It is thus necessary to test Dimebon in transgenic animal model systems to determine if and how the drug affects development and manifestation of pathology, and which pathogenic processes are altered. In the present study we treated mice harboring five familial mutations associated with hereditary AD (5xFAD line) with a chronic regime of Dimebon. The compound was not found to improve the general health or motor behavior of these mice, nor prevent accumulation of Aβ peptides in the brain. Modest changes in response to an anxiogenic task were, however, detected, suggesting Dimebon might improve behavioral abnormalities and cognition in disease in a mechanism independent of protecting against amyloidosis.
Insights
Dimebon did not prevent Alzheimer's disease (AD) pathology or improve general health in a mouse model. However, it showed potential for improving cognitive and behavioral abnormalities, possibly through mechanisms independent of amyloid plaque reduction.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Dimebon, initially an antihistamine, showed promise in early Alzheimer's disease (AD) trials but yielded mixed results in later studies.
- Evidence suggests Dimebon may possess neuroprotective properties in models of neurodegeneration.
- The exact mechanism of Dimebon's action in AD remains unclear, with proposed roles in receptor activity, mitochondrial function, and autophagy.
Purpose of the Study:
- To investigate the effects of Dimebon on the development and manifestation of AD pathology in a transgenic mouse model.
- To determine if Dimebon alters specific pathogenic processes in hereditary AD.
Main Methods:
- Treatment of 5xFAD transgenic mice (harboring five familial AD mutations) with Dimebon.
- Assessment of general health, motor behavior, amyloid-beta (Aβ) peptide accumulation, and response to an anxiogenic task.
Main Results:
- Dimebon did not improve the general health or motor behavior of 5xFAD mice.
- The compound failed to prevent the accumulation of Aβ peptides in the brain.
- Modest behavioral improvements were observed in response to an anxiogenic task, suggesting a potential cognitive benefit.
Conclusions:
- Dimebon does not appear to mitigate core Alzheimer's disease pathology, such as amyloidosis, in the 5xFAD mouse model.
- The findings suggest Dimebon may offer therapeutic benefits for cognitive and behavioral deficits in AD through pathways not directly related to amyloid reduction.
