“Tau pathology” is a major hallmark of the brains of patients with Alzheimer’s disease (AD), and one that most closely correlates with the decline of cognition in the course of disease. During Alzheimer’s disease, the protein tau changes its location inside brain cells, and we found that ectopic tau mislocalizes to the contacts between nerve cells: the synapses. We also show that tau binds to a synaptic protein called synaptogyrin-3 and that this causes important defects, including memory loss. We now found a way to undo these effects: We have developed tools to lower the expression levels of synaptogyrin-3. In this project, we propose to test these in relevant disease models by injecting human neuronal precursor cells in mice that produce lesions seen in AD. Under those conditions, these human cells die, mimicking the neurodegeneration seen in Alzheimer’s patients’ brains. We will test if our tools that lower synaptogyrin-3 expression levels protect these cells. This will define whether we are able to stop synaptic and neuronal loss. Next, we will use a mouse that expresses disease-relevant tau protein. These mice suffer from cognitive decline. We will again test if our tools are able to prevent this decline from happening. This will define whether our tools also can counteract memory loss. If we are successful, we will have created a new class of drugs that interferes with the synaptic defects that tau is inducing, paving the way for tests in human subjects.