Alzheimer's disease (AD) is characterized by the presence of Amyloid plaques which are surrounded by reactive astrocytes, activated microglia and dystrophic neurites. Dystrophic neurites (DNs) refer to damaged and swollen dendrites and axons in the region surrounding plaques. DNs are recognizable either by antibodies against p-tau, ubiquitin and other proteins or staining by silver staining methods. We have now found that RTN3, a protein initially identified as a negative modulator of BACE1, accumulates in the brains of AD patients and APP transgenic mice in a distinct population of DNs called RTN3 Immunoreactive Dystrophic Neurites (RIDNs). These results suggest the existence of various populations of DNs distinguished by the presence of specific proteins in AD brains. Biochemical characterizations suggest that RIDNs contain RTN3 in the form of high molecular weight aggregates and the formation of RIDNs correlates with the expression level of RTN3. Remarkably, we have demonstrated that transgenic mice expressing the RTN3 transgene (Tg-RTN3) develop morphologically similar RIDNs in their hippocampus. The importance of RIDNs in relation to cognitive decline is manifested by the finding that the Tg-RTN3 mice have impaired spatial memory and synaptic plasticity, indicating that identification of inhibitors of RTN3 aggregation will be important for developing an alternative therapeutic approach to the Alzheimer's cognition. More importantly, our recent in vivo study confirms that increased expression of RTN3 will reduce amyloid deposition in mouse cortex but not hippocampus. This regional disparity is due to the occurrence of RTN3 aggregates and RIDNs in the hippocampus of transgenic mice expressing RTN3, suggesting that preformed RIDNs adversely affect amyloid deposition. Altogether, our results suggest that inhibition of amyloid deposition may not be sufficient to improve cognitive function if RIDNs are still present. Hence, the most effective therapy for AD should include blocking the formation of neuritic dystrophy. Since BACE1 only interacts with RTN3 monomer but not RTN3 aggregates, we hypothesize that inhibition of RTN3 aggregation will not only block the formation of RIDNs but also increase the level of RTN3 monomer, which in turn reduces amyloid deposition. The current proposal aims to take advantage of our ability to detect biochemically tractable HMW-RTN3 and to study the in vivo effect of an inhibitor of RTN3 aggregation on the formation of RIDNs. We have developed in vitro assays for screening inhibitors of RTN3 aggregation, and this will allow us to screen small molecule inhibitor library to identify potent inhibitor of RTN3 aggregation. The identified inhibitors will be tested for their efficacies in the generated animal models. The ultimate goal is to determine the potential therapeutic application of the inhibitor in reducing cognitive failure in AD animal models.