Cerebrovascular dysfunction and cardiovascular risk factors in Alzheimer’s disease (AD) and Cerebral Amyloid Angiopathy (CAA).
Our studies focus on establishing the mechanisms responsible for vascular endothelial cell death in Alzheimer’s disease and in the aging brain, which is often also subjected to cardiovascular/cerebrovascular risk factors such as hypertension, high levels of homocysteine, and hypoperfusion.
Our previous research assessed the effects of different variants of Amyloid b (Aβ) on neurovascular cell death pathways. These variants are linked to different forms of the disease, presenting with parenchymal and/or vascular deposition, and resulting preferentially in dementia and/or cerebral hemorrhage. Our work showed that different Aβ variants triggered mitochondrial apoptotic pathways with different kinetics, parallel to their aggregation propensity and to the formation of intermediate oligomeric and protofibrillar forms of the peptides, which are responsible for the apoptotic outcome. Different Aβ aggregation species such as oligomers and protofibrils also cause differential effects on the blood brain barrier (BBB), being preferentially associated with either endothelial cell death or BBB permeability.
We are currently evaluating how the presence of cardiovascular risk factors and cerebral hypoperfusion contribute to these mechanisms, and if the actions of these different challenges on neurovascular cells are synergistic in nature.
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 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 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.
Targeting carbonic anhydrases in AD
Our research pioneered the use of the carbonic anhydrase inhibitors (CAI) methazolamide (MTZ) and acetazolamide (ATZ) to prevent Aβ-induced mitochondrial dysfunction in neurovascular cells. MTZ and ATZ are FDA-approved for different indications (such as glaucoma and high altitude sickness), and could be rapidly tested in controlled clinical trials in AD. Using these carbonic anhydrase inhibitors we prevented mitochondrial dysfunction, caspase activation and cell death in in vitro studies, as well as after acute brain Aβ injection in mice and in transgenic animal models of cerebral amyloidosis. We recently reported specific mitochondrial mechanisms responsible for this protection. We are currently aiming to expand these studies to models including tauopathy, and to investigate how particular isoforms of carbonic anhydrases (which are increased in the brain and in the mitochondria during aging and neurodegeneration) are relevant for AD pathology.
Study of biomarkers for AD, TBI and PTSD.
Our lab is also conducting multiple translational studies for biomarker discovery, focusing on the identification of biofluid biomarkers for Alzheimer’s disease, traumatic brain injury (TBI), and posttraumatic stress disorder (PTSD), in collaboration with clinical studies and centers, such as the NYU Alzheimer’s disease Center. Important collaborating projects include Dr. de Leon’s studies on AD-clearance and normal aging; Dr. Marmar’s studies on TBI, PTSD and AUD; Dr. Girardin’s studies on CV risk, sleep and neurodegeneration; among others. For these studies, we use well established assays for CSF biomarkers, as well as a novel technologies for the detection of blood biomarkers at very low concentrations, including the ultrasensitive Quanterix Simoa technology that is present in our lab at the ACT.