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 language | English |
|---|---|
| Pages (from-to) | 1018-1029 |
| Number of pages | 12 |
| Journal | Journal of Neuropathology and Experimental Neurology |
| Volume | 71 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2012 |
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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
Cite this
Hippocampal ProNGF signaling pathways and β-amyloid levels in mild cognitive impairment and alzheimer disease. / Mufson, Elliott J.; He, Bin; Nadeem, Muhammad; Perez, Sylvia E.; Counts, Scott E.; Leurgans, Sue; Fritz, Jason; Lah, James; Ginsberg, Stephen D.; Wuu, Joanne; Scheff, Stephen W.
In: Journal of Neuropathology and Experimental Neurology, Vol. 71, No. 11, 01.11.2012, p. 1018-1029.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Hippocampal ProNGF signaling pathways and β-amyloid levels in mild cognitive impairment and alzheimer disease
AU - Mufson, Elliott J.
AU - He, Bin
AU - Nadeem, Muhammad
AU - Perez, Sylvia E.
AU - Counts, Scott E.
AU - Leurgans, Sue
AU - Fritz, Jason
AU - Lah, James
AU - Ginsberg, Stephen D.
AU - Wuu, Joanne
AU - Scheff, Stephen W.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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.
AB - 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.
KW - Alzheimer disease
KW - Amyloid
KW - Mild cognitive impairment
KW - Nerve growth factor
KW - ProNGF
KW - Protein kinases
KW - TrkA
UR - http://www.scopus.com/inward/record.url?scp=84871204757&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871204757&partnerID=8YFLogxK
U2 - 10.1097/NEN.0b013e318272caab
DO - 10.1097/NEN.0b013e318272caab
M3 - Article
C2 - 23095849
AN - SCOPUS:84871204757
VL - 71
SP - 1018
EP - 1029
JO - American Journal of Psychotherapy
JF - American Journal of Psychotherapy
SN - 0002-9564
IS - 11
ER -