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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Dysregulation of brain-derived neurotrophic factor (BDNF)/full-length TrkB (TrkB-TK+) signaling is linked to neurodegeneration in Alzheimer's disease (AD).
• Truncated TrkB isoforms (TrkB-TK-, TrkB-Shc) can modulate BDNF/TrkB-TK+ signaling, with all isoforms originating from alternative transcripts.

Purpose of the Study:

• To investigate alterations in the expression of three main TrkB alternative transcripts (TrkB-TK+, TrkB-TK-, TrkB-Shc) in Alzheimer's disease (AD) brains.
• To determine if TrkB-Shc expression is modulated by amyloid beta 1-42 (Aβ(42)) and to assess its cellular impact on BDNF signaling.

Main Methods:

• Analysis of TrkB transcript levels in hippocampus, temporal cortex, occipital cortex, and cerebellum from control and AD brains (n=29).
• Assessment of truncated TrkB protein levels.
• In vitro study using differentiated SHSY5Y neuronal cell-lines exposed to Aβ(42).
• Evaluation of TrkB-Shc co-localization and its effect on BDNF/TrkB-TK+-mediated signaling pathways (MEK and protein kinase B).

Main Results:

• A specific increase in the neuron-specific TrkB-Shc transcript was observed in the AD hippocampus.
• No significant changes in TrkB-TK+ and TrkB-TK- transcript levels were detected in any brain region examined in AD.
• Increased TrkB-Shc mRNA levels were found in neuronal cell-lines exposed to Aβ(42).
• Overexpression of TrkB-Shc selectively attenuated BDNF/TrkB-TK+-mediated signaling via the MEK pathway, but not the protein kinase B pathway.

Conclusions:

• Neuron-specific alterations in TrkB expression, particularly increased TrkB-Shc, occur in the AD hippocampus.
• Elevated TrkB-Shc may represent a compensatory survival mechanism in neurons during AD pathogenesis.
• Increased MEK signaling in AD, potentially influenced by TrkB-Shc, is linked to abnormal cytoskeletal phosphorylation.