Abstract
TDP-43 proteinopathy, initially associated with ALS and FTD, is also found in 30–60% of Alzheimer’s disease (AD) cases and correlates with worsened cognition and neurodegeneration. A major component of this proteinopathy is depletion of this RNA-binding protein from the nucleus, which compromises repression of non-conserved cryptic exons in neurodegenerative diseases. To test whether nuclear depletion of TDP-43 may contribute to the pathogenesis of AD cases with TDP-43 proteinopathy, we examined the impact of depletion of TDP-43 in populations of neurons vulnerable in AD, and on neurodegeneration in an AD-linked context. Here, we show that some populations of pyramidal neurons that are selectively vulnerable in AD are also vulnerable to TDP-43 depletion in mice, while other forebrain neurons appear spared. Moreover, TDP-43 depletion in forebrain neurons of an AD mouse model exacerbates neurodegeneration, and correlates with increased prefibrillar oligomeric Aβ and decreased Aβ plaque burden. These findings support a role for nuclear depletion of TDP-43 in the pathogenesis of AD and provide strong rationale for developing novel therapeutics to alleviate the depletion of TDP-43 and functional antemortem biomarkers associated with its nuclear loss.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 859-873 |
| Number of pages | 15 |
| Journal | Acta Neuropathologica |
| Volume | 132 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 1 2016 |
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ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Clinical Neurology
- Cellular and Molecular Neuroscience
Cite this
Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer’s mouse model. / LaClair, Katherine D.; Donde, Aneesh; Ling, Jonathan P.; Jeong, Yun Ha; Chhabra, Resham; Martin, Lee J; Wong, Philip Chun.
In: Acta Neuropathologica, Vol. 132, No. 6, 01.12.2016, p. 859-873.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer’s mouse model
AU - LaClair, Katherine D.
AU - Donde, Aneesh
AU - Ling, Jonathan P.
AU - Jeong, Yun Ha
AU - Chhabra, Resham
AU - Martin, Lee J
AU - Wong, Philip Chun
PY - 2016/12/1
Y1 - 2016/12/1
N2 - TDP-43 proteinopathy, initially associated with ALS and FTD, is also found in 30–60% of Alzheimer’s disease (AD) cases and correlates with worsened cognition and neurodegeneration. A major component of this proteinopathy is depletion of this RNA-binding protein from the nucleus, which compromises repression of non-conserved cryptic exons in neurodegenerative diseases. To test whether nuclear depletion of TDP-43 may contribute to the pathogenesis of AD cases with TDP-43 proteinopathy, we examined the impact of depletion of TDP-43 in populations of neurons vulnerable in AD, and on neurodegeneration in an AD-linked context. Here, we show that some populations of pyramidal neurons that are selectively vulnerable in AD are also vulnerable to TDP-43 depletion in mice, while other forebrain neurons appear spared. Moreover, TDP-43 depletion in forebrain neurons of an AD mouse model exacerbates neurodegeneration, and correlates with increased prefibrillar oligomeric Aβ and decreased Aβ plaque burden. These findings support a role for nuclear depletion of TDP-43 in the pathogenesis of AD and provide strong rationale for developing novel therapeutics to alleviate the depletion of TDP-43 and functional antemortem biomarkers associated with its nuclear loss.
AB - TDP-43 proteinopathy, initially associated with ALS and FTD, is also found in 30–60% of Alzheimer’s disease (AD) cases and correlates with worsened cognition and neurodegeneration. A major component of this proteinopathy is depletion of this RNA-binding protein from the nucleus, which compromises repression of non-conserved cryptic exons in neurodegenerative diseases. To test whether nuclear depletion of TDP-43 may contribute to the pathogenesis of AD cases with TDP-43 proteinopathy, we examined the impact of depletion of TDP-43 in populations of neurons vulnerable in AD, and on neurodegeneration in an AD-linked context. Here, we show that some populations of pyramidal neurons that are selectively vulnerable in AD are also vulnerable to TDP-43 depletion in mice, while other forebrain neurons appear spared. Moreover, TDP-43 depletion in forebrain neurons of an AD mouse model exacerbates neurodegeneration, and correlates with increased prefibrillar oligomeric Aβ and decreased Aβ plaque burden. These findings support a role for nuclear depletion of TDP-43 in the pathogenesis of AD and provide strong rationale for developing novel therapeutics to alleviate the depletion of TDP-43 and functional antemortem biomarkers associated with its nuclear loss.
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UR - http://www.scopus.com/inward/citedby.url?scp=84992346874&partnerID=8YFLogxK
U2 - 10.1007/s00401-016-1637-y
DO - 10.1007/s00401-016-1637-y
M3 - Article
C2 - 27785573
AN - SCOPUS:84992346874
VL - 132
SP - 859
EP - 873
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 6
ER -