Hippocampal ProNGF signaling pathways and β-amyloid levels in mild cognitive impairment and alzheimer disease
Document Type
Article
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 © 2012 by the American Association of Neuropathologists, Inc.
Keywords
Alzheimer disease, Amyloid, Mild cognitive impairment, Nerve growth factor, ProNGF, Protein kinases, TrkA
Publication Date
11-1-2012
Publication Title
Journal of Neuropathology and Experimental Neurology
ISSN
00223069
E-ISSN
15546578
Volume
71
Issue
11
First Page
1018
Last Page
1029
PubMed ID
23095849
Digital Object Identifier (DOI)
10.1097/NEN.0b013e318272caab
Recommended Citation
Mufson, Elliott J.; He, Bin; Nadeem, Muhammad; Perez, Sylvia E.; Counts, Scott E.; Leurgans, Sue; Fritz, Jason; Lah, James; Ginsberg, Stephen D.; Wuu, Joanne; and Scheff, Stephen W., "Hippocampal ProNGF signaling pathways and β-amyloid levels in mild cognitive impairment and alzheimer disease" (2012). Translational Neuroscience. 1630.
https://scholar.barrowneuro.org/neurobiology/1630