No alteration in tau exon 10 alternative splicing in tangle-bearing neurons of the Alzheimer's disease brain.
Defective splicing of tau mRNA, promoting a shift between tau isoforms with (4R tau) and without (3R tau) exon 10, is believed to be a pathological consequence of certain tau mutations causing frontotemporal dementia. By assessing protein and mRNA levels of 4R tau and 3R tau in 27 AD and 20 control temporal cortex, we investigated whether altered tau splicing is a feature also in Alzheimer's disease (AD). However, apart from an expected increase of sarcosyl-insoluble tau in AD, there were no significant differences between the groups. Next, by laser-capture microscopy and quantitative PCR, we separately analyzed CA1 hippocampal neurons with and without neurofibrillary pathology from six of the AD and seven of the control brains. No statistically significant differences in 4R tau/3R tau mRNA were found between the different subgroups. Moreover, we confirmed the absence of significant ratio differences in a second data set with laser-captured entorhinal cortex neurons from four AD and four control brains. Finally, the 4R tau/3R tau ratio in CA1 neurons was roughly half of the ratio in temporal cortex, indicating region-specific differences in tau mRNA splicing. In conclusion, this study indicated region-specific and possibly cell-type-specific tau splicing but did not lend any support to overt changes in alternative splicing of tau exon 10 being an underlying factor in AD pathogenesis.
Ingelsson
Martin
M
Harvard Medical School, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. martin.ingelsson@pubcare.uu.se
Ramasamy
Karunya
K
Cantuti-Castelvetri
Ippolita
I
Skoglund
Lena
L
Matsui
Toshifumi
T
Orne
Jennifer
J
Kowa
Hasimoto
H
Raju
Susan
S
Vanderburg
Charles R
CR
Augustinack
Jean C
JC
de Silva
Rohan
R
Lees
Andrew J
AJ
Lannfelt
Lars
L
Growdon
John H
JH
Frosch
Matthew P
MP
Standaert
David G
DG
Irizarry
Michael C
MC
Hyman
Bradley T
BT
D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D016875:tau Proteins