Distribution of tdp-43 pathology in hippocampal synaptic relays suggests transsynaptic propagation in frontotemporal lobar degeneration

Pouya Jamshidi, Garam Kim, Ryan K. Shahidehpour, Kabriya Bolbolan, Tamar Gefen, Eileen H. Bigio, Marek Marsel Mesulam, Changiz Geula*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Hyperphosphorylation, nuclear depletion, and aggregation of TDP-43 in ubiquitinated inclusions is a hallmark of frontotemporal lobar degeneration (FTLD-TDP). Evidence of potential spread of TDP-43 along synaptic connections in the human is largely limited to qualitative and semiquantitative observations. We quantitatively investigated potential transsynaptic propagation of TDP-43 across the well-established chain of single synaptic connections of the hippocampus. Hippocampi from 5 participants with clinical diagnoses of primary progressive aphasia and 2 participants with behavioral variant frontotemporal dementia, all with postmortem diagnoses of FTLD-TDP, were examined. TDP-43-positive mature (darkly stained) and pre-inclusions (diffuse puncta or fibrillar staining) in the granule cell layer of dentate gyrus (DG) and pyramidal cell layers of Cornu Ammonis (CA)3, CA2, and CA1 were quantified using unbiased stereology. The density of mature TDP-43 inclusions was higher in the DG than in the CA fields (p<0.05). There were no differences in inclusion densities across the CA fields. TDP-43 pre-inclusions densities were not different across the 4 subregions. There was significantly higher preinclusion density than mature inclusions in CA3, but not in other subregions. Analysis of normalized total counts in place of densities revealed virtually identical results. Our finding of greatest mature inclusion deposition in the DG, coupled with more preinclusions than mature inclusions at the next relay station (CA3), and reduced densities of both in CA2-CA1, provide evidence in support of a sequential transsynaptic propagation mechanism of TDP-43 aggregates.

Original languageEnglish (US)
Pages (from-to)585-591
Number of pages7
JournalJournal of neuropathology and experimental neurology
Volume79
Issue number6
DOIs
StatePublished - 2020

Keywords

  • Frontotemporal lobar degeneration (FTLD)
  • Hippocampus
  • Primary progressive aphasia (PPA)
  • Prion-like
  • TDP-43

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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