. Impaired short-term plasticity in mossy fiber synapses caused by mitochondrial dysfunction of dentate granule cells is the earliest synaptic deficit in a mouse model of Alzheimer's disease. J Neurosci. 2012 Apr 25;32(17):5953-63. PubMed.

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  1. These two studies cover different aspects of oxidative stress. The Brewer group showed that wild-type mice as well as 3x transgenic mice developed oxidative changes that could be ameliorated with nicotinamide. The Ho group showed calcium-dependent changes in oxidative state in dentate/hippocampal circuits, correlating with reactive oxygen species (ROS) production and treatable with Trolox. Neither group examined human brain tissue.

    With a number of cautions (especially in extrapolating from mice to humans), these studies add support to the potential for antioxidant interventions as a preventive strategy for AD, although they do not discount the possibility that antioxidant pathways or damage may be important throughout the course of the disease. There are many other pathways that can be implicated in oxidative mechanisms for AD, as highlighted in a previous Alzforum story (see ARF related news story) and associated comments. Whether to intervene with broad-based, non-specific antioxidants (e.g., vitamin E and vitamin C, or Trolox, as used in the Ho study) or try to target specific pathways or cellular compartments is not known. The sobering responses from human clinical trials conducted to date suggest that new antioxidants with clear evidence of brain penetration would help us to further test our ability to intervene to reduce oxidative stress.

    It is worth bearing in mind that non-drug interventions, for example, exercise or diet, that are starting to be studied as interventions in AD possibly work, in part, through reducing oxidative stress.

    View all comments by Douglas Galasko

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  1. In Mice, Oxidative Changes Come Early and Antioxidants Work