Alzheimer-associated neuronal thread protein mediated cell death is linked to impaired insulin signaling.
Alzheimer-associated neuronal thread protein, AD7c-NTP, accumulates in cortical neurons and co-localizes with phospho-tau-containing cytoskeletal lesions in brains with AD. Over-expression of AD7c-NTP results in increased neuronal death mediated by apoptosis and mitochondrial dysfunction. Empirical studies demonstrating differential growth factor responses to AD7c-NTP led to us to further investigate the effects of insulin, insulin-like growth factor, type 1 (IGF-1), nerve growth factor (NGF), and platelet-derived growth factor (PDGF) stimulation on neuronal survival mechanisms in relation to AD7c-NTP expression. PNET2 human CNS-derived neuronal cells were stably transfected with a cDNA encoding AD7c-NTP or chloramphenicol acetyl transferase (CAT) whereby gene expression was regulated by an inducible promoter. In cells that expressed AD7c-NTP, insulin or IGF-1 stimulation was associated with reduced viability with increased levels of p53, p21/Waf-1, phospho-JNK, and phospho-tau, and reduced levels of Bcl-2 and phospho-Erk MAPK. In contrast, AD7c-NTP-transfected cells stimulated with NGF or PDGF, and CAT-transfected cells stimulated with any one of the four growth factors remained viable and had low levels of p53, p21/Waf-1, phospho-JNK, and phospho-tau, and abundant Bcl-2 and phospho-Erk expression. The results suggest that reduced survival in neurons that over-express AD7c-NTP may be mediated by impaired insulin/IGF-1 signaling, and that CNS neurons with abundant insulin or IGF-1 receptors may be particularly vulnerable to the adverse effects of AD7c-NTP.
de la Monte
Suzanne M
SM
Department of Medicine, Rhode Island Hospital and Brown Medical School, Providence, RI 02903, USA. Suzanne_DeLaMonte_MD@Brown.edu
Wands
Jack R
JR
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D019254:Genes, bcl-2 / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051847:Lithostathine; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*
C497612:AD7c-NTP protein, human; D000911:Antibodies, Monoclonal; D002135:Calcium-Binding Proteins; D018076:DNA, Complementary; D007328:Insulin; D051847:Lithostathine; D009419:Nerve Tissue Proteins; D010982:Platelet-Derived Growth Factor; D007334:Insulin-Like Growth Factor I; D020932:Nerve Growth Factor