title: Hippocampal proNGF signaling pathways and β-amyloid levels in mild cognitive impairment and Alzheimer disease.
abstract: Hippocampal precursor of nerve growth factor (proNGF)/NGF signaling occurs in conjunction with β-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-Akt-to-Akt 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-JNK-to-JNK ratio increased significantly in AD compared with those in NCI and MCI. Expression levels of Aβ(1-40), Aβ(1-42), and Aβ(40/42) 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.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. emufson@rush.edu
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Muhammad
authors.initials: M
authors.lastname: Nadeem
authors.forename: Sylvia E
authors.initials: SE
authors.lastname: Perez
authors.forename: Scott E
authors.initials: SE
authors.lastname: Counts
authors.forename: Sue
authors.initials: S
authors.lastname: Leurgans
authors.forename: Jason
authors.initials: J
authors.lastname: Fritz
authors.forename: James
authors.initials: J
authors.lastname: Lah
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ginsberg
authors.forename: Joanne
authors.initials: J
authors.lastname: Wuu
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scheff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D060825:Cognitive Dysfunction / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D020932:Nerve Growth Factor / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism*; D011498:Protein Precursors / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011498:Protein Precursors; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C061397:pro-nerve growth factor, human; D020932:Nerve Growth Factor