Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease
Article first published online: 15 MAR 2006
Journal of Neurochemistry
Volume 97, Issue 2, pages 475–487, April 2006
How to Cite
Ginsberg, S. D., Che, S., Wuu, J., Counts, S. E. and Mufson, E. J. (2006), Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease. Journal of Neurochemistry, 97: 475–487. doi: 10.1111/j.1471-4159.2006.03764.x
- Issue published online: 15 MAR 2006
- Article first published online: 15 MAR 2006
- Received November 22, 2005; revised manuscript received January 3, 2006; accepted January 9, 2006.
- mild cognitive impairment;
- nucleus basalis;
- RNA amplification;
Dysfunction of cholinergic basal forebrain (CBF) neurons of the nucleus basalis (NB) is a cardinal feature of Alzheimer's disease (AD) and correlates with cognitive decline. Survival of CBF neurons depends upon binding of nerve growth factor (NGF) with high-affinity (trkA) and low-affinity (p75NTR) neurotrophin receptors produced within CBF neurons. Since trkA and p75NTR protein levels are reduced within CBF neurons of people with mild cognitive impairment (MCI) and mild AD, trkA and/or p75NTR gene expression deficits may drive NB degeneration. Using single cell expression profiling methods coupled with custom-designed cDNA arrays and validation with real-time quantitative PCR (qPCR) and in situ hybridization, individual cholinergic NB neurons displayed a significant down regulation of trkA, trkB, and trkC expression during the progression of AD. An intermediate reduction was observed in MCI, with the greatest decrement in mild to moderate AD as compared to controls. Importantly, trk down regulation is associated with cognitive decline measured by the Global Cognitive Score (GCS) and the Mini-Mental State Examination (MMSE). In contrast, there is a lack of regulation of p75NTR expression. Thus, trk defects may be a molecular marker for the transition from no cognitive impairment (NCI) to MCI, and from MCI to frank AD.