Most neurodegenerative disorders are characterized by distinct patterns of misfolding and aggregation of specific proteins. Hence, neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis are considered protein misfolding disorders, or proteinopathies. Another important factor in the etiology of neurodegenerative disorders is aging, but how aging and protein misfolding lead to neurodegeneration remains largely unclear. There is currently no effective therapy to reduce the rate of neuronal loss for any of the neurodegenerative proteinopathies. Recent research trends in neurodegeneration include investigating the toxic effects of misfolded protein oligomers and the spreading mechanism of protein misfolding.
Increasing evidence suggests that, in many neurodegenerative disorders, misfolded proteins may transmit across different brain regions along axonal projections, analogous to the known spreading of prion proteins. We investigated such possibilities in the human brain by looking for misfolded tau proteins at neuronal synapses. In the postmortem brain tissue of AD subjects, many synapses are found to contain oligomers of misfolded tau. Abnormal tau proteins accumulating at both presynaptic and the postsynaptic terminals are potential substrates for transmitting tauopathy. Interestingly, non-demented elderly with classical AD symptoms (amyloid plaques and tau-bearing tangles) do not show tau oligomers depositing within synapses, implying that synaptic tau oligomers may be the key component of protein toxicity in AD.