Alzheimer’s Disease Tau Consortium: The Role of Amyloid Beta-Induced Membrane Damage in Tau Pathology

Two protein pathologies occur in Alzheimer’s disease brains: the accumulation of amyloid beta in extracellular plaques and the 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 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 an 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 surrounding plaques contain high calcium levels and become sites where tau tangles may form, which may then spread to other parts of the neuron or other cells.

To study this process, we will express a small, antibody-based protein that can bind the plaques and prevent interaction with nearby cells, protecting them. We will determine if this prevents the calcium increase and the buildup of tau pathology and spread. We will also investigate what proteins and what forms of pathological tau accumulate in the DN. Last, we will use a fluorescent protein to detect the tau seeds that cause tau to spread from cell to cell to determine if these seeds appear in dystrophic neurites and spread from neurite to neurite or from dystrophic neurites back to the cell body. Understanding how and where amyloid plaques cause tau seeds and pathology can help develop drugs to block these processes.