Preventing Formation of Reticulon 3 Immunoreactive Dystrophic Neurites Improves Cognitive Function in Mice

Neuritic dystrophy is one of the important pathological features associated with amyloid plaques in Alzheimer's disease (AD) and age-dependent neuronal dysfunctions. We reported previously that reticulon-3 (RTN3) immunoreactive dystrophic neurites (RIDNs) are abundantly present in the hippocampus of AD patients, in AD mouse models, and in aged wild-type mice. Transgenic mice overexpressing the human RTN3 transgene spontaneously develop RIDNs in their hippocampi, and the formation of RIDNs correlates with the appearance of RTN3 aggregation. To further elucidate whether the formation of RIDNs is reversible, we generated transgenic mice expressing wild-type human RTN3 under the control of a tetracycline-responsive promoter. Treatment with doxycycline for 2 months effectively turned off expression of the human RTN3 transgene, confirming the inducible nature of the system. However, the formation of hippocampal RIDNs was dependent on whether the transgene was turned off before or after the formation of RTN3 aggregates. When transgenic human RTN3 expression was turned off at young age, formation of RIDNs was essentially eliminated compared with the vehicle-treated transgenic mice. More importantly, a fear conditioning study demonstrated that contextual associative learning and memory in inducible transgenic mice was improved if the density of RIDNs was lowered. Additional mechanistic study suggested that a reduction in BDNF levels in transgenic mice might contribute to the reduced learning and memory in transgenic mice overexpressing RTN3. Hence, we conclude that age-dependent RIDNs cannot be effectively cleared once they have formed, and we postulate that successful prevention of RIDN formation should be initiated before RTN3 aggregation.