title: Amyloid beta selectively modulates neuronal TrkB alternative transcript expression with implications for Alzheimer's disease.
abstract: Dysregulation in brain-derived neurotrophic factor (BDNF)/full-length TrkB (TrkB-TK+) signaling is implicated in promoting neurodegeneration in Alzheimer's disease (AD). BDNF/TrkB-TK+ signaling can be modulated by the presence of truncated TrkB isoforms (TrkB-TK-, TrkB-Shc). All TrkB isoforms are encoded by different alternative transcripts. In this study, we assessed if expression of the three main TrkB alternative transcripts, TrkB-TK+, TrkB-TK-, and TrkB-Shc are altered in AD. Using a cohort of control and AD brains (n=29), we surveyed the hippocampus, temporal cortex, occipital cortex, and cerebellum and found specific increases in TrkB-Shc, a neuron-specific transcript, in the AD hippocampus. No significant changes were detected in TrkB-TK+ and TrkB-TK- transcript levels in AD in any brain region examined. Corresponding changes in truncated TrkB protein levels were found in the hippocampus, although a significant increase in the temporal cortex was also observed. Our findings suggested that neuron-specific changes in TrkB may be occurring in AD; thus, we determined whether TrkB-Shc expression could be modulated by amyloid beta 1-42 (Aβ(42)). We found increased TrkB-Shc mRNA levels in differentiated SHSY5Y neuronal cell-lines exposed to fibril-containing Aβ(42) preparations. When we assessed the cellular impact of increased TrkB-Shc, we found co-localization between TrkB-Shc and TrkB-TK+. Interestingly, TrkB-Shc overexpression selectively attenuated BDNF/TrkB-TK+-mediated signaling via the mitogen-activated protein kinase kinase (MEK) pathway, but not the protein kinase B pathway. In AD, MEK signaling is increased in vulnerable neurons and linked to abnormal phosphorylation of cytoskeletal proteins. Altogether, our findings suggest that elevated TrkB-Shc expression in AD may function as a compensatory response in neurons in AD to promote survival.
authors.affiliation: Illawarra Health and Medical Research Institute, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. jwong@uow.edu.au
authors.forename: J
authors.initials: J
authors.lastname: Wong
authors.forename: M
authors.initials: M
authors.lastname: Higgins
authors.forename: G
authors.initials: G
authors.lastname: Halliday
authors.forename: B
authors.initials: B
authors.lastname: Garner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002460:Cell Line; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D018625:Microscopy, Atomic Force; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D020033:Protein Isoforms; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D020033:Protein Isoforms; D020813:Receptor, trkB