Alpha7 nicotinic receptor up-regulation in cholinergic basal forebrain neurons in Alzheimer disease.
BACKGROUND
Dysfunction of basocortical cholinergic projection neurons of the nucleus basalis (NB) correlates with cognitive deficits in Alzheimer disease (AD). Nucleus basalis neurons receive cholinergic inputs and express nicotinic acetylcholine receptors (nAChRs) and muscarinic AChRs (mAChRs), which may regulate NB neuron activity in AD. Although alterations in these AChRs occur in the AD cortex, there is little information detailing whether defects in nAChR and mAChR gene expression occur in cholinergic NB neurons during disease progression.


OBJECTIVE
To determine whether nAChR and mAChR gene expression is altered in cholinergic NB neurons during the progression of AD.


METHODS
Individual NB neurons from subjects diagnosed ante mortem as having no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild to moderate AD were analyzed by single-cell AChR expression profiling via custom-designed microarrays.


METHODS
Academic research.


METHODS
Participants were members of the Rush Religious Orders Study cohort.


METHODS
Real-time quantitative polymerase chain reaction was performed to validate microarray findings.


RESULTS
Cholinergic NB neurons displayed a statistically significant up-regulation of alpha7 nAChR messenger RNA expression in subjects with mild to moderate AD compared with those with NCI and MCI (P<.001). No differences were found for other nAChR and mAChR subtypes across the cohort. Expression levels of alpha7 nAChRs were inversely associated with Global Cognitive Score and with Mini-Mental State Examination performance.


CONCLUSIONS
Up-regulation of alpha7 nAChRs may signal a compensatory response to maintain basocortical cholinergic activity during AD progression. Alternatively, putative competitive interactions of this receptor with beta-amyloid may provide a pathogenic mechanism for NB dysfunction. Increasing NB alpha7 nAChR expression may serve as a marker for the progression of AD.
Counts
Scott E
SE
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
He
Bin
B
Che
Shaoli
S
Ikonomovic
Milos D
MD
DeKosky
Steven T
ST
Ginsberg
Stephen D
SD
Mufson
Elliott J
EJ
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001479:Basal Ganglia / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000473:pathology; D003072:Cognition Disorders / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009483:Neuropsychological Tests; D020411:Oligonucleotide Array Sequence Analysis; D010275:Parasympathetic Nervous System / Q000378:metabolism* / Q000473:pathology; D011569:Psychiatric Status Rating Scales; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011978:Receptors, Nicotinic / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; D018076:DNA, Complementary; D005819:Genetic Markers; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor