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 enzyme-linked immunosorbent assay (ELISA). Hippocampal proNGF was significantly greater in AD compared to NCI and MCI cases. TrkA was significantly reduced in MCI compared to NCI and AD, whereas p75
NTR
, sortilin, and neurotrophin receptor homolog-2 remained stable. Akt decreased from NCI to MCI to AD, whereas phospho-Akt and phosphor-Akt to Akt ratio were elevated in AD compared to MCI and NCI. No differences were found in phospho-Erk, Erk or their ratio across groups. c-jun kinase (JNK) remained stable across groups, while phospho-JNK and the phospho-JNK to JNK ratio increased significantly in AD compared to 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, though 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 pro-apoptotic pathways, and that this is independent of Aβ accumulation during AD progression.
