P3‐170: TrkB alternative transcript expression in Alzheimer's disease

Brain-derived neurotrophic factor (BDNF) signaling is vital for neuronal differentiation, growth, survival, and plasticity. In Alzheimer's disease (AD), alterations in hippocampal mRNA and protein expression of the BDNF receptor, tropomyosin-related kinase B (TrkB), have been reported. While most studies report decreases in full length TrkB (TrkB-TK+) and increases in tyrosine kinase-lacking truncated TrkB (TrkB-TK-) expression, gene expression changes of other TrkB receptor isoforms, including the neuron-specific TrkB-Shc and newly characterized exon 17-skipped TrkB-D17, have yet to be described. In this study, we examine TrkB-Shc and TrkB-D17 mRNA expression in the brains of patients with AD as well as in an AD mouse model with early AD pathology; the latter used to determine whether changes in TrkB isoform expression occur before the onset of significant pathology or cognitive decline. Using a cohort of n=6/6 controls and AD cases; and a cohort of n=10/10 C57/B6 wild-type and APP/PS1 transgenic mice, we measured TrkB-TK+, TrkB-TK-, TrkB-Shc, and TrkB-D17 mRNA expression in the hippocampus and cerebellum by quantitative real-time PCR. Using pan-TrkB primers, we found elevated TrkB mRNA expression in the hippocampus of AD patients (p=0.04). When we screened for individual TrkB transcripts, we observed no significant change in TrkB-TK+ mRNA, but found significant increases in truncated TrkB transcripts including TrkB-TK- (consistent with previous findings) (p=0.03) and TrkB-Shc (p=0.004), as well as the exon 17-skipped TrkB-D17 (p=0.04). No significant change was observed for the same transcripts in the cerebellum. In two-month old APP/PS1 transgenic mice (which have yet to develop significant pathology or cognitive deficits), we found significant increases in TrkB-Shc mRNA levels (p=0.03) but no change in TrkB-TK- or TrkB-D17. Increased transcript levels of the neuron-specific TrkB-Shc in the hippocampus of AD patients and young APP/PS1 mice suggest TrkB-Shc may represent a gene expression marker of AD. Because TrkB-TK- and TrkB-D17 are known to be expressed in glia, increased expression of these transcripts in the hippocampus of AD patients but lack of change in young APP/PS1 mice implies that increases in TrkB-TK- and TrkB-D17 may be associated with gliosis in senile plaques during the later stages of AD.