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TDP-43 Related Neuropathologies and Phosphorylation State: Associations with Age and Clinical Dementia in the Cambridge City over-75s Cohort.

Accepted version
Peer-reviewed

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Type

Article

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Authors

Hokkanen, Suvi RK 
Keage, Hannah AD 
Minett, Thais 

Abstract

Pathologies associated with the Tar-DNA binding protein 43 KDa (TDP-43) are associated with neurodegenerative diseases and aging. Phosphorylation of cellular proteins is a well-accepted mechanism of biological control and can be associated with disease pathways. Phosphorylation state associated with TDP-43 associated pathology has not been investigated with respect to dementia status in a population representative sample. TDP-43 immunohistochemistry directed toward phosphorylated (TDP-43P) and unphosphorylated (TDP-43U) was assessed in sections of hippocampus and temporal cortex from 222 brains donated to the population representative Cambridge City over-75s Cohort. Relationships between dementia status and age at death for TDP-43 immunoreactive pathologies by phosphorylation state were investigated. TDP-43 pathologies are common in the oldest old in the population and often do not conform to MacKenzie classification. Increasing age is associated with glial (TDP-43P) and neuronal inclusions (TDP-43P and TDP-43U), neurites, and granulovacuolar degeneration (GVD). Dementia status is associated with GVD and glial (TDP-43 P) and neural inclusions (TDP-43 P and U). Dementia severity was associated with glial (TDP-43P) and neuronal inclusions (TDP-43U and TDP-43P), GVD, and neurites. The associations between dementia severity and both glial cytoplasmic inclusions and GVD were independent from other pathologies and TDP-43 neuronal cytoplasmic inclusions. TDP-43 pathology contributes to dementia status and progression in a variety of ways in different phosphorylation states involving both neurons and glia, independently from age and from classic Alzheimer-related pathologies. TDP-43 pathologies as cytoplasmic inclusions in neurons or glia or as GVD contribute independently to dementia.

Description

Keywords

Aging, TAR-DNA binding protein of 43 kDa, dementia, hippocampus, phosphorylation, population study, Age Factors, Aged, 80 and over, Aging, Dementia, Female, Hippocampus, Humans, Inclusion Bodies, Male, Nerve Degeneration, Neurofibrillary Tangles, Neurons, Phosphorylation, TDP-43 Proteinopathies

Journal Title

J Alzheimers Dis

Conference Name

Journal ISSN

1387-2877
1875-8908

Volume Title

75

Publisher

IOS Press

Rights

All rights reserved
Sponsorship
MRC (via University of Sheffield) (RA 124745)
National Health and Medical Research Council (NHMRC) (via University of South Australia) (LEG18399 - RG72411)
Paul G Allen Family Foundation (12076)
We thank all the participants, their families, and carers in the CC75C study. CC75C is a member study of the Cambridgeshire and Peterborough Collaboration for Leadership in Applied Health Research and Care (CLAHRC). This work was funded by the Addenbrooke’s Charitable Trust. The Cambridge Brain Bank Laboratory (which processed all CC75C cases) is supported by the National Institute for Health Research, Cambridge Biomedical Research Centre. CB and SHu were supported by NIHR Senior Investigators grant. Shu is additionally supported by a Network Support Grant awarded by the ARUK and the Paul G. Allen Foundation. SHo was supported by an ARUK funded PhD studentship. HK was supported by NHMRC grants GNT1042889 and GNT1135676. Thais Minett was funded by an Academic Clinical Fellowship from National Institute for Health Research.