Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease

Stephen D. Ginsberg, Shaoli Che, Joanne Wuu, Scott E. Counts, Elliott J. Mufson

Research output: Contribution to journalArticle

170 Citations (Scopus)

Abstract

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 (p75 NTR) 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 p75 NTR 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.

Original languageEnglish
Pages (from-to)475-487
Number of pages13
JournalJournal of Neurochemistry
Volume97
Issue number2
DOIs
StatePublished - Apr 1 2006
Externally publishedYes

Fingerprint

Gene expression
Cholinergic Agents
Neurons
Alzheimer Disease
Down-Regulation
Gene Expression
Nerve Growth Factor Receptors
Nerve Growth Factor
Nerve Growth Factor Receptor
Complementary DNA
Cognitive Dysfunction
Basal Forebrain
Oligonucleotide Array Sequence Analysis
In Situ Hybridization
Defects
Real-Time Polymerase Chain Reaction
Proteins

Keywords

  • Microarray
  • Mild cognitive impairment
  • Neurotrophin
  • Nucleus basalis
  • RNA amplification
  • trkA

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease. / Ginsberg, Stephen D.; Che, Shaoli; Wuu, Joanne; Counts, Scott E.; Mufson, Elliott J.

In: Journal of Neurochemistry, Vol. 97, No. 2, 01.04.2006, p. 475-487.

Research output: Contribution to journalArticle

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