The MPIs for this proposal independently co-developed and thoroughly characterized some of the most commonly used mouse models for research on Alzheimer’s disease and related disorders (ADRD); however, all existing tau and/or amyloid mouse models still have shortcomings which limit their utility and the questions that they can be used to answer. For example, the rTg4510 model which expresses human P301L tau through a doxycline-repressible system is one of the gold standard models in the field; however, rTg4510 is limited, in part, by its dependence on two unlinked transgenes, the early onset of tauopathy and cognitive dysfunction, and the leakiness of the tau expression. The overall goal of this proposal is to develop new models for the Alzheimer’s Disease field that overcome the shortcomings of existing models, ultimately providing an innovative platform in which the sequential nature of amyloidosis and tauopathy and the molecular pathways underlying their interaction can be examined in a streamlined, cost-effective manner. Under Aim 1, we propose to generate a model in which the CamKII-tetracycline transactivator transgene and the tau responder transgene (either WT or P301L) required for the conditional expression of tau will be co-injected and thus co-integrated into the murine genome which can subsequently transmit as a single allele. We will strive to develop a P301L tau/tTA model that will develop pre-tangle pathology at 12-15 months and tangles at 18 months of age. This new model will subsequently be fully characterized biochemically, pathologically, cognitively and structurally using MRI. Once established, these novel, conditional tau transgenics will provide a less expensive, more accessible model that develops tauopathy in mid to late life; enabling both studies aimed at accelerating and at slowing/abrogating the tauopathy. We also anticipate that this model, like the JNPL3 and rTg4510 tau models, will develop neuroinflammation and secondary TDP-43 proteinopathy. Under Aim 2, we propose to create a new conditional APP transgenic model through co-injection/co-integration using the cumate-repressible system to control APPswe/ind expression. No mouse model utilizes the cumate-repressible system in the brain and simply having the APP transgene under this alternatively conditional system positions this model for use in studies to identify interactions between APP and tau, ?-synuclein or other potential interactors. Finally, under Aim 3, we will crossbreed the new, single allele, tetracycline-repressible tau model with the single allele, cumate- repressible APP to allow the dissection of the interaction between tau (tauopathy) and APP (amyloidosis) in a sequential and systematic fashion. This innovative model, requiring a cost-effective, single breeding, permits independent control of both the tau and APP transgenes and will position the field to fill critical gaps in knowledge that no existing animal model in the AD arena currently allows.