Two protein pathologies occur in Alzheimer’s disease brains—accumulation of amyloid beta in extracellular plaques and formation of tau neurofibrillary tangles inside neurons. After amyloid plaques build up for many years, tau pathology takes off and leads to neuron death and memory loss. The focus of our project is to understand how amyloid may cause tau tangles, with the goal of blocking this process for therapeutic purposes. Structures around amyloid plaques called dystrophic neurites (DNs) consist of swollen dysfunctional axons that are filled with vesicles and proteins that are not being properly transported. We think that contact with amyloid plaques, especially areas where the plaque is growing, damages the membrane of neurons and causes uncontrolled influx of calcium ions, which is very disruptive to neuronal function and causes the formation of DNs. Calcium changes the activity of enzymes called kinases and phosphatases, which add and remove phosphate groups, respectively, to other proteins, such as tau, potentially altering their shape, function and ability to interact with other proteins. When tau is excessively phosphorylated, it self-aggregates to form tau tangles. Therefore, we hypothesize that DNs that surround plaques contain high calcium levels and become sites where tau tangles may form, which then may spread to other parts of the neuron or other cells. To study this process, we will increase or decrease the amount of actively growing amyloid fibrils in the brains of mice that are genetically engineered to develop amyloid plaques. We will determine whether increased amyloid fibril growth causes greater DN formation, tau phosphorylation and tau spreading, while decreased fibril growth reduces these outcomes. We also will increase the expression of a protein called annexin A6 that repairs damaged cell membranes, which will block the injury caused by growing amyloid fibrils and decrease DN formation, tau phosphorylation and tau spreading. We anticipate that annexin A6 could be used to prevent amyloid plaques from causing membrane damage and creating the tau tangles that lead to neuron death in the brain. We also will block specific kinases in the brain that can phosphorylate tau to inhibit tau spreading.