Co-pathologies modify hippocampal protein accumulation patterns in neurodegenerative diseases

Koji Yoshida, Shelley L. Forrest, Shojiro Ichimata, Hidetomo Tanaka, Tomoya Kon, Gabor G. Kovacs*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

INTRODUCTION: Limited research has extensively analyzed neurodegenerative disease–related protein deposition patterns in the hippocampus. METHODS: This study examined the distribution of proteins in hippocampal subregions across major neurodegenerative diseases and explored their relation to each other. The area density of phosphorylated tau (p-tau), amyloid beta (Aβ), α-synuclein, and phosphorylated TDP-43 protein deposits together with pyramidal cell density in each hippocampal subregion, including CA1-4, prosubiculum (ProS), and subiculum was assessed in 166 cases encompassing various neurodegenerative diseases. RESULTS: Alzheimer's disease-associated p-tau predominated in ProS, Aβ in the CA1, and Lewy body–related α-synuclein in the CA2. The area density of protein deposits increased with the pathological stage until a peak, then decreased in cases with high pathology stages along with pyramidal cell density. Comorbid protein pathology influenced protein deposition patterns. DISCUSSION: This comprehensive evaluation reveals characteristic neurodegenerative disease–related protein accumulation patterns in hippocampal subregions modified by co-pathologies. Highlights: Alzheimer's disease–related phosphorylated tau predominates in the prosubiculum. Amyloid beta predominates in the CA1 and Lewy body–related α-synuclein in the CA2. The area density of protein deposition increases with the disease stage up to a peak. In the high pathology stage, protein deposition and pyramidal cell density decreases. Comorbid protein pathology affects the pattern of protein accumulation.

Original languageEnglish
Article numbere14355
JournalAlzheimer's and Dementia
Volume21
Issue number1
DOIs
StatePublished - 2025/01

Keywords

  • Alzheimer's disease
  • Lewy body disease
  • TDP-43
  • alpha-synuclein
  • amyloid beta
  • corticobasal degeneration
  • hippocampus
  • limbic predominant age-related TDP-43 encephalopathy neuropathological change
  • phosphorylated tau
  • progressive supranuclear palsy

ASJC Scopus subject areas

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

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