Amyloid beta selectively modulates neuronal TrkB alternative transcript expression with implications for Alzheimer's disease

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.