title: Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer's mouse model.
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.
authors: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD, 21205, USA.|Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors: Katherine D
authors: KD
authors: LaClair
authors: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD, 21205, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors: Aneesh
authors: A
authors: Donde
authors: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD, 21205, USA.
authors: Jonathan P
authors: JP
authors: Ling
authors: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD, 21205, USA.|Neural Development and Disease Department, Korea Brain Research Institute, Daegu, 701-300, Korea.
authors: Yun Ha
authors: YH
authors: Jeong
authors: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD, 21205, USA.
authors: Resham
authors: R
authors: Chhabra
authors: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD, 21205, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors: Lee J
authors: LJ
authors: Martin
authors: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 558, Baltimore, MD, 21205, USA. wong@jhmi.edu.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. wong@jhmi.edu.|Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. wong@jhmi.edu.
authors: Philip C
authors: PC
authors: Wong
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001343:Autophagy / Q000235:genetics; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000209:etiology*; D058225:Plaque, Amyloid / Q000209:etiology / Q000235:genetics / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D016548:Prosencephalon / Q000473:pathology; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018931:Antineoplastic Agents, Hormonal; D004268:DNA-Binding Proteins; D053764:Presenilin-1; D013629:Tamoxifen; C578077:Tardbp protein, mouse
keywords: Alzheimer’s disease; Forebrain; Nuclear depletion; TDP-43; β-Amyloid