Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

Janssen M Kotah; Mandy S J Kater; Niek Brosens; Sylvie L Lesuis; Roberta Tandari; Thomas M Blok; Luca Marchetto; Ella Yusaf; Frank T W Koopmans; August B Smit; Paul J Lucassen; Harm J Krugers; Mark H G Verheijen; Aniko Korosi

doi:10.1002/alz.13569

Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

Janssen M Kotah, Mandy S J Kater, Niek Brosens, Sylvie L Lesuis, Roberta Tandari, Thomas M Blok, Luca Marchetto, Ella Yusaf, Frank T W Koopmans, August B Smit, Paul J Lucassen, Harm J Krugers, Mark H G Verheijen, Aniko Korosi

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

INTRODUCTION: Early-life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid-beta (Aβ) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear.

METHODS: We studied how ES affects the hippocampal synaptic proteome in wild-type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence.

RESULTS: The hippocampal synaptosomes of both ES-exposed WT and early-stage APP/PS1 mice showed a relative decrease in actin dynamics-related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins.

DISCUSSION: Our data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD.

Original language	English
Pages (from-to)	1637-1655
Journal	Alzheimer's & dementia : the journal of the Alzheimer's Association
Volume	20
Issue number	3
Early online date	6 Dec 2023
DOIs	https://doi.org/10.1002/alz.13569
Publication status	Published - Mar 2024

Bibliographical note

Funding

The authors thank Aline Mak for assistance with EM sample preparation, Miguel Gonzalez‐Lozano and Jan van Weering for help with EM analysis, Yvonne Gouwenberg for synaptosome isolations and Iryna Paliukhovich and Remco Klaassen for technical assistance with MS sample preparation and MS data analysis. P.J.L., M.S.J.K., M.H.G.V., H.K., A.B.S., and A.K. are supported by Alzheimer Nederland and by the Zon‐MW Memorabel MODEM program, T.M.B. by an ENW‐M1 grant of the Dutch Research Council (NWO), and PJL by the Center for Urban Mental Health, UvA.

Funders	Funder number
Center for Urban Mental Health
Universiteit van Amsterdam
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Alzheimer Nederland

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Kotah, J. M., Kater, M. S. J., Brosens, N., Lesuis, S. L., Tandari, R., Blok, T. M., Marchetto, L., Yusaf, E., Koopmans, F. T. W., Smit, A. B., Lucassen, P. J., Krugers, H. J., Verheijen, M. H. G., & Korosi, A. (2024). Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism. Alzheimer's & dementia : the journal of the Alzheimer's Association, 20(3), 1637-1655. https://doi.org/10.1002/alz.13569

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title = "Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism",

abstract = "INTRODUCTION: Early-life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid-beta (Aβ) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear.METHODS: We studied how ES affects the hippocampal synaptic proteome in wild-type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence.RESULTS: The hippocampal synaptosomes of both ES-exposed WT and early-stage APP/PS1 mice showed a relative decrease in actin dynamics-related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins.DISCUSSION: Our data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD.",

author = "Kotah, {Janssen M} and Kater, {Mandy S J} and Niek Brosens and Lesuis, {Sylvie L} and Roberta Tandari and Blok, {Thomas M} and Luca Marchetto and Ella Yusaf and Koopmans, {Frank T W} and Smit, {August B} and Lucassen, {Paul J} and Krugers, {Harm J} and Verheijen, {Mark H G} and Aniko Korosi",

note = "{\textcopyright} 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

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doi = "10.1002/alz.13569",

language = "English",

volume = "20",

pages = "1637--1655",

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Kotah, JM, Kater, MSJ, Brosens, N, Lesuis, SL, Tandari, R, Blok, TM, Marchetto, L, Yusaf, E, Koopmans, FTW , Smit, AB, Lucassen, PJ, Krugers, HJ, Verheijen, MHG & Korosi, A 2024, 'Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism', Alzheimer's & dementia : the journal of the Alzheimer's Association, vol. 20, no. 3, pp. 1637-1655. https://doi.org/10.1002/alz.13569

Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism. / Kotah, Janssen M; Kater, Mandy S J; Brosens, Niek et al.
In: Alzheimer's & dementia : the journal of the Alzheimer's Association, Vol. 20, No. 3, 03.2024, p. 1637-1655.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

AU - Kotah, Janssen M

AU - Kater, Mandy S J

AU - Brosens, Niek

AU - Lesuis, Sylvie L

AU - Tandari, Roberta

AU - Blok, Thomas M

AU - Marchetto, Luca

AU - Yusaf, Ella

AU - Koopmans, Frank T W

AU - Smit, August B

AU - Lucassen, Paul J

AU - Krugers, Harm J

AU - Verheijen, Mark H G

AU - Korosi, Aniko

PY - 2024/3

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N2 - INTRODUCTION: Early-life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid-beta (Aβ) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear.METHODS: We studied how ES affects the hippocampal synaptic proteome in wild-type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence.RESULTS: The hippocampal synaptosomes of both ES-exposed WT and early-stage APP/PS1 mice showed a relative decrease in actin dynamics-related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins.DISCUSSION: Our data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD.

AB - INTRODUCTION: Early-life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid-beta (Aβ) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear.METHODS: We studied how ES affects the hippocampal synaptic proteome in wild-type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence.RESULTS: The hippocampal synaptosomes of both ES-exposed WT and early-stage APP/PS1 mice showed a relative decrease in actin dynamics-related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins.DISCUSSION: Our data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD.

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DO - 10.1002/alz.13569

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C2 - 38055782

SN - 1552-5260

VL - 20

SP - 1637

EP - 1655

JO - Alzheimer's & dementia : the journal of the Alzheimer's Association

JF - Alzheimer's & dementia : the journal of the Alzheimer's Association

IS - 3

ER -

Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

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