Understanding the role of chronic stress as a risk factor for Alzheimer’s disease

Alzheimer’s disease (AD), the leading cause of dementia, affects nearly 44 million people worldwide and costs over $600 billion/year (1% of the world’s GDP). Although considerable progress has been made in its understanding, AD remains a complex disease with poorly defined initiators and no effective treatments, highlighting the urgent need to identify precipitating factors, diagnostic biomarkers, and innovative therapeutic approaches. Epidemiological and clinical studies suggest that stressful life events as well as high levels of stress hormones, glucocorticoids (GC), are implicated in the onset of AD. Unfortunately, very little is known about how environmental stress contributes to precipitation of AD. Based on both preclinical and clinical evidence, this project clarifies the different cellular mechanisms through which chronic stress precipitates AD brain pathology impacting on different cell types such as neurons, microglia, astrocyte combining multiscale analytical platforms that incorporates detailed molecular, neurostructural (3D reconstruction), ultrastructural (electron microscopy), proteomic, electrophysiological and behavioral analyses coupled with novel cell-based assays for intracellular trafficking and cell signaling (e.g. proximity ligand assay, flow cytometry coupled with fluorescence timer tagged on Tau protein, RNAScope) and single-cell multi-omics.

Funding Agency

Project Reference

Project Members

Main Project Outcomes

S. Queirós, “Right ventricular segmentation in multi-view cardiac MRI using a unified U-net model”, in E. Puyol Antón et al. (eds) Statistical Atlases and Computational Models of the Heart. Multi-Disease, Multi-View, and Multi-Center Right Ventricular Segmentation in Cardiac MRI Challenge. STACOM 2021. Lecture Notes in Computer Science, vol 13131, pp. 287-295, Springer, Cham, 2022.

“Best Paper Award in the M&Ms-2 Challenge”, by M&Ms2 Challenge organizers and the Medical Image Computing and Computer Assisted Intervention (MICCAI) Society.

Main Project Outcomes

1. Zhuravleva V, Vaz-Silva J, Zhu M, Gomes P, Silva JM, Sousa N, Sotiropoulos I, Waites CL. “Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production.” Cell Death Dis. 2021 12(12):1137. doi: 10.1038/s41419-021-04433-w.

2. Monteiro F*†, Sotiropoulos I*†, Carvalho O, Sousa N and Silva FS. “Multi‑mechanical waves against Alzheimer’s disease pathology: a systematic review” Translat Neurodegeneration 2021 Sep 24;10(1):36. doi: 10.1186/s40035-021-00256-z.

3. Monteiro-Fernandes D, Silva JM, Soares-Cunha C, Dalla C, Kokras N, François A, Billiras R, Bretin S, Sousa N, Sotiropoulos I* “Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in Stress and Aβ-evoked hippocampal pathology” Molecular Psychiatry 2020 May 28. doi: 10.1038/s41380-020-0794-5.

4. Sotiropoulos I*, Silva JM, Gomes P, Sousa N, Almeida OFX “Stress and the etiopathogenesis of Alzheimer’s disease and depression” Adv Exp Med Biol. 2019;1184:241-257. doi: 10.1007/978-981-32-9358-8_20

5. Silva J, Rodrigues S, Sampaio-Marques B, Gomes P, Neves-Carvalho A, Dioli C, Soares-Cunha C, Takashima A, Ludovico P, Wolozin B, Sousa N, Sotiropoulos I* “Dysregulation of autophagy and Stress granule-related proteins in stress-driven Tau pathology”. Cell Death Diff 2019 doi: 10.1038/s41418-018-0217-1.

6. Vaz-Silva J, Gomes P, Quintremil S, Zhu M, Zhuravleva V, Meira T, Silva J, Dioli C, Soares-Cunha C, Daskalakis N, Sousa N, Sotiropoulos I*, Waites C* (equal contribution) “Endo-lysosomal sorting and degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction”. EMBO 2018 doi 10.15252/embj.20189908

7. Vyas S, Rodrigues AJ, Silva JM, Tronche F, Almeida OFX, Sousa N, Sotiropoulos I*. (2016) Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration. Neural Plasticity 2016:6391686.

8. Sotiropoulos I*, Sousa N. Tau as the converging protein between chronic stress and Alzheimer’s disease synaptic pathology Neurodegenrative diseases (2016) 16(1-2), pp. 22–25.

9. Sotiropoulos I*, Silva J, Kimura T, Rodrigues A.J, Costa P, Almeida OFX, Sousa N, Takashima A. (2015) “Female hippocampus vulnerability to environmental stress as precipitating factor in Tau aggregation pathology” J Alzheimer´s Dis 43(3):763-74.

10. Sotiropoulos I, Catania C, Pinto LG, Silva R, Pollerberg GE, Takashima A, Sousa N. Almeida OFX. (2011) ”Stress acts cumulatively to precipitate Alzheimer´s disease-like TAU pathology and cognitive deficits ”. J Neuroscience 31:7840-7.