Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease.
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 p75(NTR) protein levels are reduced within CBF neurons of people with mild cognitive impairment (MCI) and mild AD, trkA and/or p75(NTR) 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.
Ginsberg
Stephen D
SD
Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, Orangeburg, USA. ginsberg@nki.rfmh.org
Che
Shaoli
S
Wuu
Joanne
J
Counts
Scott E
SE
Mufson
Elliott J
EJ
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003072:Cognition Disorders / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D008609:Mental Status Schedule / Q000706:statistics & numerical data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011180:Postmortem Changes; D016548:Prosencephalon / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012720:Severity of Illness Index
C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D020917:Receptor, trkA