Regional Increase in the Expression of the BCAT Proteins in Alzheimer's Disease Brain: Implications in Glutamate Toxicity

Background: The human branched chain aminotransferases (hBCATm, mitochondrial and hBCATc, cytosolic) are major contributors to brain glutamate production. This excitatory neurotransmitter is thought to contribute to neurotoxicity in neurodegenerative conditions such as Alzheimer's disease (AD) but the expression of hBCAT in this disease has not previously been investigated. Objective: The objective of investigating hBCAT expression is to gain insight into potential metabolic pathways that may be dysregulated in AD brain, which would contribute to glutamate toxicity. Methods: Western blot analysis and immunohistochemistry were used to determine the expression and localization of hBCAT in postmortem frontal and temporal cortex from AD and matched control brains. Results: Western blot analysis demonstrated a significant regional increase in hBCATc expression in the hippocampus (↑ 36%; p-values of 0.012), with an increase of ↑ 160% reported for hBCATm in the frontal and temporal cortex (p-values = 4.22 × 10-4 and 2.79 × 10-5, respectively) in AD relative to matched controls, with evidence of post-translational modifications to hBCATm, more prominent in AD samples. Using immunohistochemistry, a significant increase in immunopositive labelling of hBCATc was observed in the CA1 and CA4 region of the hippocampus (p-values = 0.011 and 0.026, respectively) correlating with western blot analysis. Moreover, the level of hBCATm in the frontal and temporal cortex correlated significantly with disease severity, as indicated by Braak staging (p-values = 5.63 × 10-6 and 9.29 × 10-5, respectively). Conclusion: The expression of the hBCAT proteins is significantly elevated in AD brain. This may modulate glutamate production and toxicity, and thereby play a role in the pathogenesis of the disease.