Defining the Presynaptic Molecular Switch Linking Amyloid Pathology to Tau Pathogenesis

The mechanism connecting the accumulation of amyloid beta to the initiation of tau pathology remains one of the most critical that has yet to be fully elucidated by the AD field. Many believe that, since cognitive decline correlates much more strongly with tau pathology compared to amyloid pathology, halting the transition from amyloid to tau would be immensely impactful for patients. Dr. Savas has worked to understand this mechanism for some time and has focused his attention on a part of the neuron called the presynapse. The presynapse, as its name suggests, is the part of the neuron on the sending side of a synapse and is where the neurotransmitters are released from that trigger the various signals from one neuron to the next. Dr. Savas has previously shown that the presynapse is the site of the breakdown of a protein quality control process called proteostasis. This breakdown of proteostasis in turn has been linked with the accumulation of misfolded tau proteins that can act as the initiators of tau aggregation, leading to their designation as “tau seeds”.

With that work drawing his focus to the presynapse, Dr. Savas’ project now aims to identify how amyloid beta is acting at the presynapse to drive the production of tau seeds. The first aim of the project will leverage a new mouse model that more accurately reflects the transition from amyloid to tau than previous models. The goal with these mice is to identify the minute changes happening at the presynapses of these mice as amyloid beta begins to accumulate and eventually lead to the production of tau. Capturing the molecular snapshot of that transition will be critical in informing future experiments for targeted therapeutic development. The second aim will then reduce amyloid pathology in these mice and again capture the changes occurring, or not occurring compared to the first aim, to confirm which changes are truly attributable to the amyloid pathology. Ultimately, this project seeks to define a long-elusive mechanism that sits at the heart of AD research and identify specific targets for potential therapeutic intervention to stop the transition from amyloid to tau pathology.