Mitochondria, caspases and death receptors in Aβ-induced brain vascular degeneration
Our studies identified for the first time the TRAIL Death Receptors DR4 and DR5 as specific targets for Aβ oligomers binding in cerebral microvascular endothelial cells, demonstrating that DR4/5 were activated after Aβ challenge, and triggered extrinsic apoptotic pathways with involvement of mitochondrial dysfunction and caspase 8/9 activation. Aβ oligomers and protofibrils specifically functioned as alternative ligands for these receptors. These studies unveiled new targets for the protection of vascular cells against neurodegeneration, neuroinflammation, and vascular dysfunction in Alzheimer’s disease (AD), including death receptors, mitochondrial dysfunction, and caspase activation pathways. We are currently testing if the presence of homocysteine or low oxygen and glucose affect these pathways in an additive or synergistic manner or if complementary cell death pathways are activated.
In addition to cell death pathways, our studies focus on mitochondrial function and metabolism and its deregulation in the presence of Aβ, tau, and cardiovascular risk factors.
Selected Publications:
1- Fossati S, Cam J, Meyerson J, et al. Differential activation of mitochondrial apoptotic pathways by vasculotropic amyloid-beta variants in cells composing the cerebral vessel walls. FASEB J. 2010;24(1):229-241. doi: 10.1096/fj.09-139584
2- Fossati S, Ghiso J, Rostagno A. Molecular analysis of apoptotic pathways induced by amyloid-β variants in cerebral vascular cells. Alzheimer’s & Dementia, 2010; 6: S376-S377. https://doi.org/10.1016/j.jalz.2010.05.1264
3- Fossati S, Ghiso J, Rostagno A. Insights into caspase-mediated apoptotic pathways induced by amyloid-β in cerebral microvascular endothelial cells. Neurodegener Dis. 2012;10(1-4):324-8. DOI: 10.1159/000332821. Epub 2011 Dec 7. PMID: 22156599; PMCID: PMC3363348.
4- Fossati S, Ghiso J, Rostagno A. TRAIL death receptors DR4 and DR5 mediate cerebral microvascular endothelial cell apoptosis induced by oligomeric Alzheimer's Aβ. Cell Death Dis. 2012 Jun 14;3(6):e321. DOI: 10.1038/cddis.2012.55. PMID: 22695614; PMCID: PMC3388229.
5- Fossati, S; Ghiso, J; Rostagno, A. Amyloid beta oligomers trigger death receptors-mediated apoptosis in cerebral endothelial cells. FASEB journal. 2012:26. ISSN: 0892-6638 https://doi.org/10.1096/fasebj.26.1_supplement.752.8
6- Jang S, Chapa-Dubocq XR, Fossati S, Javadov S. Analysis of Mitochondrial Calcium Retention Capacity in Cultured Cells: Permeabilized Cells Versus Isolated Mitochondria. Front Physiol. 2021 Dec 7;12:773839. DOI: 10.3389/fphys.2021.773839. PMID: 34950052; PMCID: PMC8688924.
