TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease.
OBJECTIVE
This study aimed to determine the frequency of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) in the setting of hippocampal sclerosis (HpScl) and Alzheimer's disease (AD) using immunohistochemistry for TAR DNA binding protein 43 (TDP-43), a putative marker for FTLD-U.


METHODS
Initially, 21 cases of HpScl associated with a variety of other pathological processes and 74 cases of AD were screened for FTLD-U with TDP-43 immunohistochemistry. A confirmation study was performed on 93 additional AD cases. Specificity of TDP-43 antibodies was assessed using double-immunolabeling confocal microscopy, immunoelectron microscopy, and biochemistry.


RESULTS
TDP-43 immunoreactivity was detected in 71% of HpScl and 23% of AD cases. Double immunostaining of AD cases for TDP-43 and phospho-tau showed that the TDP-43-immunoreactive inclusions were usually distinct from neurofibrillary tangles. At the ultrastructural level, TDP-43 immunoreactivity in AD was associated with granular and filamentous cytosolic material and only occasionally associated with tau filaments. Western blots of AD cases showed a band that migrated at a higher molecular weight than normal TDP-43 that was not present in AD cases without TDP-43 immunoreactivity.


CONCLUSIONS
These results suggest that as many as 20% of AD cases and more than 70% of HpScl cases have pathology similar to that found in FTLD-U. Whether this represents concomitant FTLD-U or is analogous to colocalization of alpha-synuclein and tau in AD, reflecting a propensity for codeposition of abnormal protein conformers, remains to be determined.
Amador-Ortiz
Catalina
C
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
Lin
Wen-Lang
WL
Ahmed
Zeshan
Z
Personett
David
D
Davies
Peter
P
Duara
Ranjan
R
Graff-Radford
Neill R
NR
Hutton
Michael L
ML
Dickson
Dennis W
DW
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D012598:Sclerosis; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; D025801:Ubiquitin