Distinctive temporal profiles of detergent-soluble and -insoluble tau and Aβ species in human Alzheimer’s disease

David J. Koss (Corresponding Author), Marina Dubini, Heather Buchanan, Claire Hull, Bettina Platt (Corresponding Author)

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Abstract

Alzheimer’s disease (AD) pathology relevant proteins tau and beta-amyloid (Aβ) exist as an array of post-translationally modified and conformationally altered species with varying abundance, solubility and toxicity. Insoluble neurofibrillary tau tangles and Aβ plaques are end-stage AD hallmarks, yet may carry less disease significance compared to soluble species. At present, it is unclear how soluble and insoluble tau and Aβ relate to each other as well as to disease progression. Here, detergent soluble and insoluble fractions generated from post-mortem human temporal lobe samples (Brodmann area 21) were probed for tau and Aβ markers in immuno-dot assays. Measures were quantified according to diagnosis (AD cf. Non-AD), neuropathological severity, and correlated with disease progression (Braak stages). All markers were elevated within AD cases cf. non-AD controls (p<0.05) independent of solubility. However, when considered according to neuropathological severity, phospho-tau (detected via CP13 and AT-8 antibodies) was elevated early within the soluble fraction (p<0.05 intermediate cf. low severity) and emerged only later within the insoluble fraction (p<0.05 high cf. low severity). In contrast, PHF1 phospho-tau, TOC reactive tau oligomers and amyloid markers rose within the two fractions simultaneously. Independent of solubility, cognitive correlations were observed for tau makers and for fibrillary amyloid (OC). In contrast only soluble total Aβ was significantly correlated with intellectual impairment. Following the exclusion of end-stage cases, only soluble total Aβ remained correlated with cognition. The data indicate differential rates of protein aggregation during AD progression and confirm the disease relevance of early emerging soluble Aβ species.
Original languageEnglish
Pages (from-to)121-134
Number of pages14
JournalBrain Research
Volume1699
Early online date10 Aug 2018
DOIs
Publication statusPublished - 15 Nov 2018

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Detergents
Alzheimer Disease
Solubility
Disease Progression
Amyloid
Neurofibrillary Tangles
Amyloid beta-Peptides
Temporal Lobe
Cognition
Pathology
Antibodies
Proteins

Keywords

  • Alzheimer’s disease
  • Tau
  • β-amyloid
  • Pathology
  • Aggregation

Cite this

Distinctive temporal profiles of detergent-soluble and -insoluble tau and Aβ species in human Alzheimer’s disease. / Koss, David J. (Corresponding Author); Dubini, Marina; Buchanan, Heather; Hull, Claire; Platt, Bettina (Corresponding Author).

In: Brain Research, Vol. 1699, 15.11.2018, p. 121-134.

Research output: Contribution to journalArticle

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note = "Acknowledgements We would like to deeply thank all donors and their families for the tissue provided for this study. Human tissue samples were supplied by the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK, the Alzheimer’s Society and the Medical Research Council, and sourced from the MRC London Neurodegenerative Diseases Brain Bank, the Manchester Brain Bank, the South West Dementia Brain Bank (SWDBB), the Newcastle Brain Tissue Resource and the Oxford Brain Bank. The Newcastle Brain Tissue Resource and Oxford Brain Bank are also supported by the National Institute for Health Research (NIHR) Units. The South West Dementia Brain Bank (SWDBB) receives additional support from BRACE (Bristol Research into Alzheimer's and Care of the Elderly). Antibodies CP13 and PHF1 were generously provided by Prof Peter Davies. TOC1 antibodies were a gift from Nicholas Kanaan at Michigan State University (originally created by Lester Binder at Northwestern University). Funding The work presented here was funded by Alzheimer's Research UK (Grant refs: ARUK-PPG2014A-21, ARUK-NSG2015-1 and ARUK-NCG2017A-3 to BP and DK).",
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N2 - Alzheimer’s disease (AD) pathology relevant proteins tau and beta-amyloid (Aβ) exist as an array of post-translationally modified and conformationally altered species with varying abundance, solubility and toxicity. Insoluble neurofibrillary tau tangles and Aβ plaques are end-stage AD hallmarks, yet may carry less disease significance compared to soluble species. At present, it is unclear how soluble and insoluble tau and Aβ relate to each other as well as to disease progression. Here, detergent soluble and insoluble fractions generated from post-mortem human temporal lobe samples (Brodmann area 21) were probed for tau and Aβ markers in immuno-dot assays. Measures were quantified according to diagnosis (AD cf. Non-AD), neuropathological severity, and correlated with disease progression (Braak stages). All markers were elevated within AD cases cf. non-AD controls (p<0.05) independent of solubility. However, when considered according to neuropathological severity, phospho-tau (detected via CP13 and AT-8 antibodies) was elevated early within the soluble fraction (p<0.05 intermediate cf. low severity) and emerged only later within the insoluble fraction (p<0.05 high cf. low severity). In contrast, PHF1 phospho-tau, TOC reactive tau oligomers and amyloid markers rose within the two fractions simultaneously. Independent of solubility, cognitive correlations were observed for tau makers and for fibrillary amyloid (OC). In contrast only soluble total Aβ was significantly correlated with intellectual impairment. Following the exclusion of end-stage cases, only soluble total Aβ remained correlated with cognition. The data indicate differential rates of protein aggregation during AD progression and confirm the disease relevance of early emerging soluble Aβ species.

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