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Author Notes:

Elliott J. Mufson, PhD, Professor of Neurological Sciences, Alla and Solomon Jesmer Chair in Aging, Rush University Medical Center, 1735 W. Harrison Street, Suite 300, Chicago, IL 60612. Tel: 312-563-3558; Fax: 312-563-3571; emufson@rush.edu.

The authors thank the nuns, priests, and brothers from across the country that participated in the Religious Orders Study; and Rush Alzheimer’s Disease Center staff.

The authors also thank patients and research participants at the University of Kentucky Alzheimer’s Disease Center.

The authors declare that they have no conflict of interest.

Subjects:

Research Funding:

Supported by NIA Grants PO1AG14449, PO1AG9466 and P30AG10161.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences
  • Pathology
  • Neurosciences & Neurology
  • Alzheimer disease
  • Amyloid
  • Mild cognitive impairment
  • Nerve growth factor
  • ProNGF
  • Protein kinases
  • TrkA
  • NERVE GROWTH-FACTOR
  • CHOLINERGIC BASAL FOREBRAIN
  • P75 NEUROTROPHIN RECEPTOR
  • NEURONAL APOPTOSIS
  • TAU PATHOLOGY
  • UP-REGULATION
  • SORTILIN
  • ACTIVATION
  • P75(NTR)
  • NEUROPATHOLOGY

Hippocampal ProNGF Signaling Pathways and beta-Amyloid Levels in Mild Cognitive Impairment and Alzheimer Disease

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Journal Title:

Journal of Neuropathology and Experimental Neurology

Volume:

Volume 71, Number 11

Publisher:

, Pages 1018-1029

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

Copyright © 2012 by the American Association of Neuropathologists, Inc.

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