Spatial proteomics of hippocampal subfield-specific pathology in Alzheimer's disease and primary age-related tauopathy

Jamie M. Walker, Miranda E. Orr, Timothy C. Orr, Emma L. Thorn, Thomas D. Christie, Raquel T. Yokoda, Meenakshi Vij, Alexander J. Ehrenberg, Gabriel A. Marx, Andrew T. McKenzie, Justin Kauffman, Enna Selmanovic, Thomas Wisniewski, Eleanor Drummond, Charles L. White, John F. Crary, Kurt Farrell, Tiffany F. Kautz, Elena V. Daoud, Timothy E. Richardson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

INTRODUCTION: Alzheimer's disease (AD) and primary age-related tauopathy (PART) both harbor 3R/4R hyperphosphorylated-tau (p-tau)-positive neurofibrillary tangles (NFTs) but differ in the spatial p-tau development in the hippocampus. METHODS: Using Nanostring GeoMx Digital Spatial Profiling, we compared protein expression within hippocampal subregions in NFT-bearing and non-NFT-bearing neurons in AD (n = 7) and PART (n = 7) subjects. RESULTS: Proteomic measures of synaptic health were inversely correlated with the subregional p-tau burden in AD and PART, and there were numerous differences in proteins involved in proteostasis, amyloid beta (Aβ) processing, inflammation, microglia, oxidative stress, and neuronal/synaptic health between AD and PART and between definite PART and possible PART. DISCUSSION: These results suggest subfield-specific proteome differences that may explain some of the differences in Aβ and p-tau distribution and apparent pathogenicity. In addition, hippocampal neurons in possible PART may have more in common with AD than with definite PART, highlighting the importance of Aβ in the pathologic process. Highlights: Synaptic health is inversely correlated with local p-tau burden. The proteome of NFT- and non-NFT-bearing neurons is influenced by the presence of Aβ in the hippocampus. Neurons in possible PART cases share more proteomic similarities with neurons in ADNC than they do with neurons in definite PART cases.

Original languageEnglish (US)
Pages (from-to)783-797
Number of pages15
JournalAlzheimer's and Dementia
Volume20
Issue number2
DOIs
StatePublished - Feb 2024

Keywords

  • Alzheimer's disease (AD)
  • aging
  • neurodegeneration
  • primary age-related tauopathy (PART)
  • resilience
  • resistance
  • synapses

ASJC Scopus subject areas

  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Health Policy
  • Developmental Neuroscience
  • Epidemiology

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