Neuronal gene expression in non-demented individuals with intermediate Alzheimer's Disease neuropathology.
While the clinical and neuropathological characterization of Alzheimer's Disease (AD) is well defined, our understanding of the progression of pathologic mechanisms in AD remains unclear. Post-mortem brains from individuals who did not fulfill clinical criteria for AD may still demonstrate measurable levels of AD pathologies to suggest that they may have presented with clinical symptoms had they lived longer or are able to stave off disease progression. Comparison between such individuals and those clinically diagnosed and pathologically confirmed to have AD will be key in delineating AD pathogenesis and neuroprotection. In this study, we expression profiled laser capture microdissected non-tangle bearing neurons in 6 post-mortem brain regions that are differentially affected in the AD brain from 10 non-demented individuals demonstrating intermediate AD neuropathologies (NDAD; Braak stage of II through IV and CERAD rating of moderate to frequent) and evaluated this data against that from individuals who have been diagnosed with late onset AD as well as healthy elderly controls. We identified common statistically significant expression changes in both NDAD and AD brains that may establish a degenerative link between the two cohorts, in addition to NDAD specific transcriptomic changes. These findings pinpoint novel targets for developing earlier diagnostics and preventative therapies for AD prior to diagnosis of probable AD. We also provide this high-quality, low post-mortem interval (PMI), cell-specific, and region-specific NDAD/AD reference data set to the community as a public resource.
Liang
Winnie S
WS
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA. wliang@tgen.org
Dunckley
Travis
T
Beach
Thomas G
TG
Grover
Andrew
A
Mastroeni
Diego
D
Ramsey
Keri
K
Caselli
Richard J
RJ
Kukull
Walter A
WA
McKeel
Daniel
D
Morris
John C
JC
Hulette
Christine M
CM
Schmechel
Donald
D
Reiman
Eric M
EM
Rogers
Joseph
J
Stephan
Dietrich A
DA
D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D015331:Cohort Studies; D030541:Databases, Genetic; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D042282:Microdissection / Q000379:methods; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism; D011237:Predictive Value of Tests; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012015:Reference Standards; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000378:metabolism / Q000473:pathology
D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D046988:Proteasome Endopeptidase Complex