Synaptic oligomeric tau in Alzheimer’s disease – a potential culprit in the spread of tau pathology through the brain

Summary In Alzheimer’s disease (AD), fibrillar tau pathology accumulates and spreads through the brain and synapses are lost. Evidence from mouse models indicates that tau spreads trans-synaptically from pre- to postsynapses and that oligomeric tau is synaptotoxic, but data on synaptic tau in human brain is scarce. Here we used sub-diffraction-limit microscopy to study synaptic tau accumulation in post-mortem temporal and occipital cortices of human AD and control donors. Oligomeric tau is present in both pre- and postsynaptic terminals even in areas without abundant fibrillar tau deposition. Further, there is a higher proportion of oligomeric tau compared to phosphorylated or misfolded tau found at synaptic terminals. These data suggest that accumulation of oligomeric tau in synapses is an early event in disease pathogenesis, and that tau pathology may progress through the brain via trans-synaptic spread in human disease. Thus, specifically reducing oligomeric tau at synapses may be a promising therapeutic strategy for AD.