Alzheimer’s disease (AD) is increasingly understood to begin at the synapse, the tiny communication points between neurons, long before large amounts of amyloid or tau accumulate or neurons begin to die. Healthy synapses rely on a constant cycle of clearing out old or damaged proteins and replacing them with new ones. Dr. Savas’s earlier work showed that this cycle breaks down very early in AD. In an amyloid-driven mouse model that closely reflects human biology, his team found that certain presynaptic proteins build up because they are not properly renewed. Similar changes were also seen in young people with Down syndrome, who develop Alzheimer’s pathology early in life. These findings suggest that early synaptic damage may arise from a failure of the cell’s normal protein “housekeeping” system.
Although both amyloid and tau are involved in Alzheimer’s, it remains unclear how they work together at synapses to drive early changes. Previous studies hint that tau may be required for amyloid to impair synaptic function, but this idea has not been tested in the most relevant disease models or examined using direct measurements of protein turnover. In preliminary work, the Savas team has identified multiple presynaptic proteins that accumulate in amyloid-producing mice because they are not being replaced at a normal rate. They also found structural changes in synaptic vesicles, the structures that store and release neurotransmitters, allowing neurons to communicate across the synapse. Similar protein imbalances were also observed in Down syndrome brains. Together, these results highlight a consistent and early disruption in synapse maintenance across different amyloid-related conditions. Based on these discoveries, the Savas lab hypothesizes that tau is necessary for amyloid to cause this early buildup of stalled presynaptic proteins. This rationale forms the basis of the proposed research.
They will investigate their central hypothesis using two aims. In the first aim, they will test whether reducing or removing tau prevents amyloid from causing presynaptic protein buildup. They will use tau-lowering treatments, tau knockout mice, and biochemical measurements to determine whether normal protein renewal is restored when tau levels are reduced. In the second aim, they will track how tau pathology alters the turnover of presynaptic proteins over the course of disease using metabolic labeling and mass spectrometry. By comparing healthy mice, amyloid-producing mice, and mice with modified tau levels, they aim to pinpoint the steps at which tau disrupts the cell’s protein-maintenance systems.
This research addresses fundamental questions: what goes wrong at synapses at the very start of Alzheimer’s disease, and how do amyloid and tau work together to cause this breakdown? By identifying the molecular events that destabilize synapses early on, the project has the potential to reveal new therapeutic targets aimed at preserving synaptic health and slowing or preventing cognitive decline.
