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Background  Disruption of synaptic connectivity is a significant early event in many neurodegenerative conditions affecting the aging CNS, including Alzheimer's disease and Parkinson's disease. Therapeutic approaches that protect synapses from degeneration in the aging brain offer the potential to slow or halt the progression of such conditions. A range of animal models expressing the slow Wallerian Degeneration ( Wld S  ) gene show robust neuroprotection of synapses and axons from a wide variety of traumatic and genetic neurodegenerative stimuli in both the central and peripheral nervous systems, raising that possibility that  Wld S   may be useful as a neuroprotective agent in diseases with synaptic pathology. However, previous studies of neuromuscular junctions revealed significant negative effects of increasing age and positive effects of gene-dose on  Wld S  -mediated synaptic protection in the peripheral nervous system, raising doubts as to whether  Wld S   is capable of directly conferring synapse protection in the aging brain.    Methodology/Principal Findings  We examined the influence of age and gene-dose on synaptic protection in the brain of mice expressing the  Wld S   gene using an established cortical lesion model to induce synaptic degeneration in the striatum. Synaptic protection was found to be sensitive to  Wld S   gene-dose, with heterozygous  Wld S   mice showing approximately half the level of protection observed in homozygous  Wld S   mice. Increasing age had no influence on levels of synaptic protection. In contrast to previous findings in the periphery, synapses in the brain of old  Wld S   mice were just as strongly protected as those in young mice.    Conclusions/Significance  Our study demonstrates that  Wld S  -mediated synaptic protection in the CNS occurs independently of age, but is sensitive to gene dose. This suggests that the  Wld S   gene, and in particular its downstream endogenous effector pathways, may be potentially useful therapeutic agents for conferring synaptic protection in the aging brain.

Synaptic Protection in the Brain of WldS Mice Occurs Independently of Age but Is Sensitive to Gene-Dose