Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are
composed mainly of aggregated a-synuclein phosphorylated at Ser129. Although phosphorylated a-synuclein is believed to exert
toxic effects at the synapse in dementia with Lewy bodies and other a-synucleinopathies, direct evidence for the precise synaptic
localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the
present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence
allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated a-synuclein
pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with
dementia with Lewy bodies, five patients with Alzheimer’s disease and five healthy control subjects to analyse the presence of
phosphorylated a-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed
in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A
total of 1 318 700 single pre- or post-synaptic terminals were analysed. We found that phosphorylated a-synuclein is present
exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and
small aggregates (50.16 mm3). Between 19% and 25% of phosphorylated a-synuclein deposits were found in presynaptic terminals
mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated a-synuclein
were significantly larger than those that did not. Finally, a gradient of phosphorylated a-synuclein aggregation in synapses
(pre4pre + post4post-synaptic) was observed. These results indicate that phosphorylated a-synuclein is found at the presynaptic
terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated a-synuclein aggregates that are
associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated a-synuclein
may disrupt the structure and function of the synapse in dementia with Lewy bodies.
