Early synaptic pathology is associated with small tau aggregates in Alzheimer's disease

Alzheimers disease (AD) is phenotypically characterised by progressive memory loss, which involves tau aggregation and synaptic pathology. Here we characterised the tau aggregates in individual synaptosomes from AD cases and controls measuring their number and size using single molecule fluorescence microscopy. A total of 7,888 synaptosomes from pre-frontal cortex samples were studied, showing the presence of AT8-positive tau aggregates in a small fraction of synaptosomes ([~]3%) from control brains, reaching [~]20% by Braak stage 6 with more larger aggregates. We then investigated the multi-phosphorylation of synaptic tau aggregates for AT8 and T181 and quantified the co-localisation of phosphatidylserine and CD47, synaptic "eat me" and "dont eat me" signals respectively, along with synaptogyrin-3, which contributes to tau mediated synaptic dysfunction. T181, phosphatidylserine, and synaptogyrin-3 co-localisation with AT8-positive tau were increased during stage 3 and CD47 was decreased, indicating early synaptic pathology is associated with the formation of small tau aggregates, contributing to microglia-driven synaptic loss.