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

David J. Koss; Marina Dubini; Heather Buchanan; Claire Hull; Bettina Platt

doi:10.1016/j.brainres.2018.08.014

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)

^*Corresponding author for this work

University of Aberdeen

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

15 Downloads (Pure)

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 language	English
Pages (from-to)	121-134
Number of pages	14
Journal	Brain Research
Volume	1699
Early online date	10 Aug 2018
DOIs	https://doi.org/10.1016/j.brainres.2018.08.014
Publication status	Published - 15 Nov 2018

Bibliographical 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).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Alzheimer’s disease
Tau
β-amyloid
Pathology
Aggregation

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Accepted Manuscript
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Accepted author manuscript, 1.4 MBLicence: CC BY-NC-ND

Cite this

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title = "Distinctive temporal profiles of detergent-soluble and -insoluble tau and Aβ species in human Alzheimer{\textquoteright}s disease",

abstract = "Alzheimer{\textquoteright}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.",

keywords = "Alzheimer{\textquoteright}s disease, Tau, β-amyloid, Pathology, Aggregation",

author = "Koss, \{David J.\} and Marina Dubini and Heather Buchanan and Claire Hull and Bettina Platt",

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{\textquoteright}s Research UK, the Alzheimer{\textquoteright}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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T1 - Distinctive temporal profiles of detergent-soluble and -insoluble tau and Aβ species in human Alzheimer’s disease

AU - Koss, David J.

AU - Dubini, Marina

AU - Buchanan, Heather

AU - Hull, Claire

AU - Platt, Bettina

N1 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - Tau

KW - β-amyloid

KW - Pathology

KW - Aggregation

U2 - 10.1016/j.brainres.2018.08.014

DO - 10.1016/j.brainres.2018.08.014

M3 - Article

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SN - 0006-8993

VL - 1699

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JO - Brain Research

JF - Brain Research

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

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