Reduction of cortical TrkA but not p75(NTR) protein in early-stage Alzheimer's disease.

Abstract

Degeneration of cholinergic nucleus basalis (NB) cortical projection neurons is associated with cognitive decline in late-stage Alzheimer's disease (AD). NB neuron survival is dependent on coexpression of the nerve growth factor (NGF) receptors p75(NTR) and TrkA, which bind NGF in cortical projection sites. We have shown previously a significant reduction of NB perikarya expressing p75(NTR) and TrkA protein during the early stages of AD. Whether there is a concomitant reduction in cortical levels of these receptors during the progression of AD is unknown. p75(NTR) and TrkA protein was evaluated by quantitative immunoblotting in five cortical regions (anterior cingulate, superior frontal, superior temporal, inferior parietal, and visual cortex) of individuals clinically diagnosed with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD, or severe AD. Cortical p75(NTR) levels were stable across the diagnostic groups. In contrast, TrkA levels were reduced approximately 50% in mild/moderate and severe AD compared with NCI and MCI in all regions except visual cortex. Mini-Mental Status Examination scores correlated with TrkA levels in anterior cingulate, superior frontal, and superior temporal cortex. The selective reduction of cortical TrkA levels relative to p75(NTR) may have important consequences for cholinergic NB function during the transition from MCI to AD.