Hippocampal ProNGF signaling pathways and β-amyloid levels in mild cognitive impairment and alzheimer disease

Elliott J. Mufson, Bin He, Muhammad Nadeem, Sylvia E. Perez, Scott E. Counts, Sue Leurgans, Jason Fritz, James Lah, Stephen D. Ginsberg, Joanne Wuu, Stephen W. Scheff

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Hippocampal precursor of nerve growth factor (proNGF)/NGF signaling occurs in conjunction with A-amyloid (Aβ) accumulations in Alzheimer disease (AD). To assess the involvement of this pathway in AD progression, we quantified these proteins and their downstream pathway activators in postmortem tissues from the brains of subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD using immunoblotting and ELISA. Hippocampal proNGF was significantly greater in AD cases compared with those in NCI and MCI cases. TrkA was significantly reduced in MCI compared with those in NCI and AD, whereas p75 neurotrophin receptor, sortilin, and neurotrophin receptor homolog 2 remained stable. Akt decreased from NCI to MCI to AD, whereas phospho- Akt and phospho-AktYtoYAkt ratio were elevated in AD compared with those in MCI and NCI. No differences were found in phospho- Erk, Erk, or their ratio across groups. Although c-jun kinase (JNK) remained stable across groups, phospho-JNK and the phospho- JNKYtoYJNK ratio increased significantly in AD compared with those in NCI and MCI. Expression levels of Aβ1-40, Aβ 1-42, and Aβ40/42 ratio were stable. Statistical analysis revealed a strong positive correlation between proNGF and phospho-JNK, although only proNGF was negatively correlated with cognitive function and only TrkA was negatively associated with pathologic criteria. These findings suggest that alterations in the hippocampal NGF signaling pathway in MCI and AD favor proNGF-mediated proapoptotic pathways, and that this is independent of Aβ accumulation during AD progression.

Original languageEnglish (US)
Pages (from-to)1018-1029
Number of pages12
JournalJournal of neuropathology and experimental neurology
Volume71
Issue number11
DOIs
StatePublished - Nov 1 2012

Keywords

  • Alzheimer disease
  • Amyloid
  • Mild cognitive impairment
  • Nerve growth factor
  • ProNGF
  • Protein kinases
  • TrkA

ASJC Scopus subject areas

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

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  • Cite this

    Mufson, E. J., He, B., Nadeem, M., Perez, S. E., Counts, S. E., Leurgans, S., Fritz, J., Lah, J., Ginsberg, S. D., Wuu, J., & Scheff, S. W. (2012). Hippocampal ProNGF signaling pathways and β-amyloid levels in mild cognitive impairment and alzheimer disease. Journal of neuropathology and experimental neurology, 71(11), 1018-1029. https://doi.org/10.1097/NEN.0b013e318272caab