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Int J Clin Exp Pathol 2011;4(2):147-155

Review Article
TDP-43 in aging and Alzheimer’s disease – a review

Andrea C. Wilson, Brittany N. Dugger, Dennis W. Dickson, Deng-Shun Wang

Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA;
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Received October 10, 2010; accepted January, 28, 2011; Epub January 30, 2011; published February 15, 2011

Abstract: Transactive response DNA-binding protein of 43 kDa (TDP-43), an RNA and DNA binding protein involved in transcriptional
repression, RNA splicing and RNA metabolism during the stress response, is the major component of neuronal inclusions in amyotrophic
lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions, now referred to as FTLD TDP.  While initially thought to
be relatively specific to ALS and FTLD TDP, TDP-43 pathology has now been detected in a number of other neurodegenerative diseases, many
associated with tau pathology, including Guam Parkinson dementia complex and Alzheimer’s disease (AD).  ITDP-43 pathology is detected in
25% to 50% of AD cases, especially those with more severe clinical phenotype and greater Alzheimer type pathology, as well as AD cases with
hippocampal sclerosis (HS).  HS is characterized by selective neuronal loss affecting CA1 sector of the hippocampus, and most cases of HS,
with or without AD, have TDP-43 pathology.  Whether TDP-43 pathology is merely an incidental finding in AD or actually contributing to the more
severe clinical phenotype remains unresolved.  Presence of TDP-43 in normal elderly, who are at increased risk for AD, would strengthen the
argument that it is not merely a secondary or incidental finding in end stage AD.  Limited studies suggest that TDP-43 pathology it is infrequent
in neurologically normal elderly (3% or less).  We provide an overview of what is known about TDP-43 in AD, normal aging and in other
disorders and suggest that TDP-43 proteinopathies be considered in two classes – primary and secondary. (IJCEP1010002).

Keywords: Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), neurofibrillary tangles
(NFT), progranulin, tau, transactive response DNA-binding protein 43 (TDP-43)

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Address all correspondence to:
Dr. Deng-Shun Wang
University of Wisconsin
Department of Pathology and Laboratory Medicine
School of Medicine and Public Health
1300 University Avenue (MSC 6330)
Madison, WI 53706, USA.
Tel: 608-262-9825

Dr. Dennis W. Dickson
Department of Neuroscience
Mayo Clinic, Jacksonville, FL, USA.
Tel: 904-953-7137, Fax: 904-953-7117