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The amyloidogenic potential and behavioral correlates of stress

Molecular Psychiatry volume 14, pages 95–105 (2009)Cite this article

Abstract

Observations of elevated basal cortisol levels in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids (GC) may contribute to the development and/or maintenance of AD. Consistent with that hypothesis, we show that stress and GC provoke misprocessing of amyloid precursor peptide in the rat hippocampus and prefrontal cortex, resulting in increased levels of the peptide C-terminal fragment 99 (C99), whose further proteolytic cleavage results in the generation of amyloid-β (Aβ). We also show that exogenous Aβ can reproduce the effects of stress and GC on C99 production and that a history of stress strikingly potentiates the C99-inducing effects of Aβ and GC. Previous work has indicated a role for Aβ in disruption of synaptic function and cognitive behaviors, and AD patients reportedly show signs of heightened anxiety. Here, behavioral analysis revealed that like stress and GC, Aβ administration causes spatial memory deficits that are exacerbated by stress and GC; additionally, Aβ, stress and GC induced a state of hyperanxiety. Given that the intrinsic properties of C99 and Aβ include neuroendangerment and behavioral impairment, our findings suggest a causal role for stress and GC in the etiopathogenesis of AD, and demonstrate that stressful life events and GC therapy can have a cumulative impact on the course of AD development and progression.

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Acknowledgements

We thank Dieter Fischer and Rainer Stoffel for excellent technical assistance, Carola Hetzel for administrative help, and Drs Keiro Shirotani and Ayako Yamamoto for helpful advice. Isabel Matos and Lucilia Pinto are thanked for help with histological preparation and scoring, Dr Sam Gandy for providing the 369 antibody and Dr Alexandre Patchev for help with image preparation. CC and IS were supported by stipends from the Max Planck Society and EU Marie Curie Training Fellowships (at University College London, UK). The collaboration between the German and Portuguese laboratories was supported through the German–Portuguese Luso-Alemas Program (DAAD/GRICES). This study was conducted within the framework of the EU-supported integrated project ‘CRESCENDO’ (Contract FP6-018652).

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  1. C Catania and I Sotiropoulos: These authors contributed equally to this study

Authors and Affiliations

  1. Max Planck Institute of Psychiatry, Munich, Germany

    C Catania, I Sotiropoulos, C Onofri & O F X Almeida

  2. Life and Health Science Research Institute, University of Minho, Braga, Portugal

    R Silva & N Sousa

  3. Alzheimer's Disease Research Centre, University of Dundee, Dundee, UK

    K C Breen

  4. Parkinson's Disease Society, London, UK

    K C Breen

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  1. C Catania
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Correspondence to O F X Almeida.

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Catania, C., Sotiropoulos, I., Silva, R. et al. The amyloidogenic potential and behavioral correlates of stress. Mol Psychiatry 14, 95–105 (2009). https://doi.org/10.1038/sj.mp.4002101

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