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

Abstract

Synaptic molecular characterization is limited for Alzheimers disease (AD). We used mass cytometry to quantify 38 probes in approximately 17 million single synaptic 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 synaptic 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 dementia. Our results were independently supported by multiplex ion beam imaging of intact tissue.

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

“…Montine TJ and colleagues have implemented the SynTOF technique in synaptosomes derived from nonhuman primates, PS/APP mice, and post-mortem tissue from individuals solely with AD neuropathologic change [463]. Some of the most striking findings in this study included the absence of Aβ at human synapses, diverging from prior authors' findings (e.g.…”

“…For instance, low plasmatic levels of apoE are related to a higher risk of developing dementia [770]. However, it was recently reported that low presynaptic apoE levels could be related to AD resilience [463]. Thus, it would result in significant interest in future studies to determine the influence of the altered levels of apoE isoforms in different compartments as well as which cells acting as a source of apoE, neurons, astrocytes, microglia, pericytes, and the implications of each source.…”

“…[459]. The authors also observed an increase in the hippocampal synaptic levels of the marker CD47, apoE, and a possible link between low apoE levels in pre-synaptic events and AD resilience [463]. Although one of the possible limitations of this technique is relying on optimal antibody binding, it constitutes a promising tool for future studies.…”

Single-cell Spatial Proteomic Imaging for Human Neuropathology

“…Focusing on synaptic density, we calculated synaptic positive pixels by either excitatory (SYP+, PSD95+, and either VGLUT1+ or VGLUT2+) or inhibitory (SYP+, VGAT+, GAD+) synaptic pixels. We then looked at the coincidence with PHF1-TAU and observed that while the highest percentage of PHF1-TAU formation in synapses occurred in ADD, all samples that contained the TT-region showed synaptic protein/PHF1-TAU localization (Figure 5G), similar to what we have recently reported in synaptosomes (Phongpreecha et al, 2021). Similar results were seen for Αβ plaque proximity to synaptic pixels in the AP region (Figure 5G).…”

“…We identified several molecular signatures that could have contributed to neuron survival. First, as in many animal models and recently in human tissue, we found pathologic Tau to be localized (but not exclusive) to neuronal synapses (Lemke et al, 2020;Phongpreecha et al, 2021). Drosophila to mouse studies have shown that synaptic PHF1-TAU interferes with synaptic vesicles (Sahara et al, 2014;Tai et al, 2014;Zhou et al, 2017).…”