TDP-43 in aging and Alzheimer's disease - A review

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

Research output: Contribution to journalReview article

110 Citations (Scopus)

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). TDP-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 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.

Original languageEnglish (US)
Pages (from-to)147-155
Number of pages9
JournalInternational Journal of Clinical and Experimental Pathology
Volume4
Issue number2
StatePublished - Nov 2 2011
Externally publishedYes

Fingerprint

Alzheimer Disease
Pathology
Sclerosis
Frontotemporal Dementia
Incidental Findings
Amyotrophic Lateral Sclerosis
DNA-Binding Proteins
TDP-43 Proteinopathies
Guam
Frontotemporal Lobar Degeneration
RNA Splicing
Phenotype
RNA-Binding Proteins
Ubiquitin
Neurodegenerative Diseases
Dementia
Hippocampus
RNA

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)

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology

Cite this

TDP-43 in aging and Alzheimer's disease - A review. / Wilson, Andrea C.; Dugger, Brittany; Dickson, Dennis W.; Wang, Deng Shun.

In: International Journal of Clinical and Experimental Pathology, Vol. 4, No. 2, 02.11.2011, p. 147-155.

Research output: Contribution to journalReview article

Wilson, Andrea C. ; Dugger, Brittany ; Dickson, Dennis W. ; Wang, Deng Shun. / TDP-43 in aging and Alzheimer's disease - A review. In: International Journal of Clinical and Experimental Pathology. 2011 ; Vol. 4, No. 2. pp. 147-155.
@article{f30093713c094c51bf435c4e16361fa1,
title = "TDP-43 in aging and Alzheimer's disease - A review",
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). TDP-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 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.",
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)",
author = "Wilson, {Andrea C.} and Brittany Dugger and Dickson, {Dennis W.} and Wang, {Deng Shun}",
year = "2011",
month = "11",
day = "2",
language = "English (US)",
volume = "4",
pages = "147--155",
journal = "International Journal of Clinical and Experimental Pathology",
issn = "1936-2625",
publisher = "e-Century Publishing Corporation",
number = "2",

}

TY - JOUR

T1 - TDP-43 in aging and Alzheimer's disease - A review

AU - Wilson, Andrea C.

AU - Dugger, Brittany

AU - Dickson, Dennis W.

AU - Wang, Deng Shun

PY - 2011/11/2

Y1 - 2011/11/2

N2 - 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). TDP-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 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.

AB - 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). TDP-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 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.

KW - Alzheimer's disease (AD)

KW - Amyotrophic lateral sclerosis (ALS)

KW - Frontotemporal lobar degeneration (FTLD)

KW - Neurofibrillary tangles (NFT)

KW - Progranulin

KW - Tau

KW - Transactive response DNA-binding protein 43 (TDP-43)

UR - http://www.scopus.com/inward/record.url?scp=79958098783&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79958098783&partnerID=8YFLogxK

M3 - Review article

C2 - 21326809

AN - SCOPUS:79958098783

VL - 4

SP - 147

EP - 155

JO - International Journal of Clinical and Experimental Pathology

JF - International Journal of Clinical and Experimental Pathology

SN - 1936-2625

IS - 2

ER -