Gene expression correlates of neurofibrillary tangles in Alzheimer's disease.
Neurofibrillary tangles (NFT) constitute one of the cardinal histopathological features of Alzheimer's disease (AD). To explore in vivo molecular processes involved in the development of NFTs, we compared gene expression profiles of NFT-bearing entorhinal cortex neurons from 19 AD patients, adjacent non-NFT-bearing entorhinal cortex neurons from the same patients, and non-NFT-bearing entorhinal cortex neurons from 14 non-demented, histopathologically normal controls (ND). Of the differentially expressed genes, 225 showed progressively increased expression (AD NFT neurons > AD non-NFT neurons > ND non-NFT neurons) or progressively decreased expression (AD NFT neurons < AD non-NFT neurons < ND non-NFT neurons), raising the possibility that they may be related to the early stages of NFT formation. Immunohistochemical studies confirmed that many of the implicated proteins are dysregulated and preferentially localized to NFTs, including apolipoprotein J, interleukin-1 receptor-associated kinase 1, tissue inhibitor of metalloproteinase 3, and casein kinase 2, beta. Functional validation studies are underway to determine which candidate genes may be causally related to NFT neuropathology, thus providing therapeutic targets for the treatment of AD.
Dunckley
Travis
T
Neurogenomics Division, Translational Genomics Research Institute, 445 North 5th Street, Phoenix, AZ 85004, USA.
Beach
Thomas G
TG
Ramsey
Keri E
KE
Grover
Andrew
A
Mastroeni
Diego
D
Walker
Douglas G
DG
LaFleur
Bonnie J
BJ
Coon
Keith D
KD
Brown
Kevin M
KM
Caselli
Richard
R
Kukull
Walter
W
Higdon
Roger
R
McKeel
Daniel
D
Morris
John C
JC
Hulette
Christine
C
Schmechel
Donald
D
Reiman
Eric M
EM
Rogers
Joseph
J
Stephan
Dietrich A
DA
D000369:Aged, 80 and over; D018728:Entorhinal Cortex / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism*
D009419:Nerve Tissue Proteins