Single-synapse analyses of Alzheimer’s disease implicate pathologic tau, DJ1, CD47, and ApoE

Synaptic molecular characterization is limited for Alzheimer’s disease (AD). Our newly invented mass cytometry-based method, Synaptometry by Time of Flight (SynTOF), was used to measure 38 antibody probes in approximately 17 million single-synapse events from human brains without pathologic change or with pure AD or Lewy body disease (LBD), non-human primates (NHP), and PS/APP mice. Synaptic molecular integrity in humans and NHP was similar. Although not detected in human synapses, Aβ was in PS/APP mice single-synapse events. Clustering and pattern identification of human synapses showed expected disease-specific differences, like increased hippocampal pathologic tau in AD and reduced caudate dopamine transporter in LBD, and revealed novel findings including increased hippocampal CD47 and lowered DJ1 in AD and higher ApoE in AD with dementia. Our results were independently supported by multiplex ion beam imaging of intact tissue. This highlights the higher depth and breadth of insight on neurodegenerative diseases obtainable through SynTOF.

Methods
The dataset was collected using mass cytometry at The Human Immune Monitoring Center (HIMC) and multiplexed ion beam imaging by time of flight (MIBI-TOF) at Stanford University in 2019-2020 and 2020, respectively. The single-synapse data has been processed by arcsinh transformed with a cofactor of 5 to produce the results published in Science Advances, where a detailed experimental method and preprocessing can be found.