Biology subjects

Fossati, S.

Publications and source records attributed to Fossati, S..

5 recordsLinked to original sources

bioRxiv2025

LACK OF OXYGEN AND/OR GLUCOSE DIFFERENTIALLY POTENTIATES Aβ40EQ22- AND Aβ42-INDUCED CEREBRAL ENDOTHELIAL CELL DEATH, BARRIER DYFUNCTION AND ANGIOGENESIS IMPAIRMENT

BackgroundDisrupted brain hemodynamics and cerebrovascular damage resulting in cerebral hypoperfusion occur early within Alzheimers Disease (AD) pathogenesis. Cerebral hypoperfusion is also an extremely common consequence of cardiovascular risk factors and diseases (CVRFs/CVDs), which usually manifest in midlife, when AD pathology initiates, and actively contribute to AD onset and progression. Previously our lab has demonstrated that the vasculotropic Dutch mutant, A{beta}Q22, and A{beta}42 promote endothelial cells (ECs) apoptosis, barrier permeability, and angiogenic impairments. Prior research has indicated that hypoperfusion promotes analogous EC dysfunction. A{beta} deposition occurs within a hypoperfused environment in AD, but whether exposure of cerebral ECs to A{beta} under hypoperfusion results in potentiated cerebral EC dysfunction through activation of common molecular mechanisms remained unknown. MethodsHuman cerebral ECs were treated with A{beta}40-Q22 or A{beta}42, glucose deprivation (GD), or a combination of both, under normoxia or hypoxia conditions. Cell death mechanisms (apoptosis/necrosis), endothelial barrier dysfunction/permeability (TEER/barrier-regulating proteins/proinflammatory activation), and angiogenesis impairment (vessel branching/VEGF signaling) were evaluated. ResultsReduction of glucose and/or oxygen potentiates A{beta}-induced cerebral EC death, barrier instability, junction protein dysregulation, inflammatory activation, and angiogenesis/wound healing failure. In particular, hypoperfusion exacerbates A{beta}Q22-mediated cerebral EC apoptosis, TEER/ZO1 decreases, ICAM1, IL6, and IL8 upregulation, monocyte migration, and wound healing impairments. Differentially, when in combination with A{beta}42, hypoperfusion more strongly potentiates cerebral EC necrosis as well as increases in MMP2, phosphorylated claudin-5, IFN{gamma}, and IL12p70 expression. Additionally, this study identified that GD exerts stronger effects on promoting increases in cerebral EC caspase-3 activation, apoptosis, and MMP2/ICAM1 expression, while hypoxia particularly increases necrosis, ZO1 expression, and pro-angiogenic protein expression. ConclusionsThis study reveals specific and selective mechanisms through which hypoxia, low glucose and amyloidosis mutually operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in AD/CAA comorbid with hypoperfusion conditions. HighlightsO_LIDepriving cerebral endothelial cells of glucose and/or oxygen potentiates A{beta}-induced endothelial dysfunction, differentially promoting increased cell death, barrier instability and dysregulation of blood brain barrier proteins, inflammatory activation, and angiogenesis and wound healing failure, in relation to the specific peptide and low glucose or oxygen conditions. C_LIO_LIUnder hypoperfusion conditions, A{beta}Q22 more strongly exacerbates increases in apoptosis, ICAM1, IL6, and IL8 expression, and monocyte migration and decreases in TEER, ZO1 expression, and wound healing, revealing that the vasculotropic A{beta}Q22 produces even stronger vascular effects when in combination with hypoperfusion. C_LIO_LIUnder hypoperfusion conditions, A{beta}42 more strongly potentiates increases in necrosis and MMP2, phosphorylated claudin-5, IFN{gamma}, and IL12p70 expression. C_LIO_LIGlucose deprivation exerts stronger effects on increasing caspase-3 activation, apoptosis, and MMP2 and ICAM1 expression, while hypoxia displays stronger effects on increasing necrosis and ZO1 and pro-angiogenic protein expression. C_LIO_LIWe demonstrated that A{beta}Q22 more intensely promotes vascular dysfunction when in combination with hypoperfusion conditions versus A{beta}42. C_LIO_LIverall, results from this study point to the importance of monitoring and preventing cerebral hypoperfusion particularly during midlife, when AD pathology begins to develop, to prevent this early pathology from working with A{beta} to create a more detrimental dementia trajectory, and highlights new targets for possible therapeutic or preventive strategies. C_LI

neuroscience↗

bioRxiv2024

Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis

Structured abstractO_ST_ABSINTRODUCTIONC_ST_ABSDisturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimers disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes. METHODSWe employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo MRI, to investigate early capillary dysfunction in Tg-SwDI mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances. RESULTSOur study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and Amyloid-{beta} (A{beta}) load in 9-10-month-old Tg-SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced A{beta} load. DISCUSSIONThese findings underscore the importance of capillary flow disturbances as early biomarkers in presymptomatic AD and highlight the potential of CAIs for preserving vascular integrity in the early stages of AD.

neuroscience↗

bioRxiv2023

Amyloid β induces cardiac dysfunction and neuro-signaling impairment in the heart of an Alzheimer's disease model

While a link between cardiovascular risk factors and increased Alzheimers disease (AD) risk has been reported, it remains unclear whether AD pathology has a direct effect on cardiac function and myocardial innervation. AD and amyloidosis are known to impair neuronal function and affect brain neurotrophic factors (NGF and BDNF) expression. Amyloid aggregates and neuro-signaling impairments may also expose AD patients to peripheral nervous system deficits, promoting cardiac disorders. Here, we characterize cardiac physiology, amyloid pathology, neurotrophic factors loss, and the impoverishment of cardiac neuronal fibers in Tg2576-AD mice hearts, human cardiomyocytes in culture, and human AD post-mortem left ventricular (LV) heart tissue. We reveal that Tg2576 animals exhibit increased myocardial fibrosis, amyloid {beta} (A{beta}) deposition, and brain/heart-axis neurotrophic deficiencies, resulting in myocardial denervation and cardiac dysfunction. A{beta} oligomers reduce BDNF expression in both human immortalized and iPSC-derived cardiomyocytes, by disrupting TrkB/CREB signaling. Analysis of human LV AD post-mortem tissue confirmed cell and animal results. Our findings elucidate a previously unknown mechanism of A{beta}-induced cardiac neurotrophic signaling dysregulation, underscoring the relevance of heart degeneration in AD. Translational PerspectiveThis research identified cardiac amyloid pathology, neurotrophic factor depletion, and reduced myocardial nerve function in a transgenic model of cerebral amyloidosis (Tg2576) and in human AD heart tissue. These findings carry significant diagnostic and therapeutic implications, emphasizing the role of neuro-signaling disruption in cardiac physiology impairment linked to AD. Our study advocates for considering cardiac complications in AD management and paves the way for future precision medicine approaches to enhance systemic clinical strategies for treating AD, proposing the cardiac neurotrophic signaling pathway as a potential therapeutic target.

molecular biology↗

bioRxiv2023

HOMOCYSTEINE POTENTIATES AMYLOID β-INDUCED CEREBRAL ENDOTHELIAL CELL APOPTOSIS, BLOOD BRAIN BARRIER DYSFUNCTION AND ANGIOGENIC IMPAIRMENT

Cerebrovascular dysfunction has been implicated as a major contributor to Alzheimers Disease (AD) pathology, with cerebral endothelial cell (cEC) stress promoting ischemia, cerebral-blood flow impairments and blood-brain barrier (BBB) permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), exacerbate AD pathology and risk. Yet, the underlying molecular mechanisms for this interaction remain unclear. Our lab has demonstrated that amyloid beta 40 (A{beta}40) species, and particularly A{beta}40-E22Q (vasculotropic Dutch mutant), promote death receptor 4 and 5 (DR4/DR5)-mediated apoptosis in human cECs, barrier permeability and angiogenic impairment. Previous studies show that Hhcy also induces EC dysfunction, but it remains unknown whether A{beta} and homocysteine function through common molecular mechanisms. We tested the hypotheses that Hhcy exacerbates A{beta}-induced cEC DR4/5-mediated apoptosis, barrier dysfunction, and angiogenesis defects. This study was the first to demonstrate that Hhcy specifically potentiates A{beta}40-E22Q-mediated activation of the DR4/5-mediated extrinsic apoptotic pathway in cECs, including DR4/5 expression, caspase 8/9/3 activation, cytochrome-c release and DNA fragmentation. Additionally, we revealed that Hhcy intensifies the deregulation of the same cEC junction proteins mediated by A{beta}, precipitating BBB permeability. Furthermore, Hhcy and A{beta}40-E22Q, impairing VEGF-A/VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decrease cEC angiogenic capabilities. Overall, these results show that the presence of the CV risk factor Hhcy exacerbates A{beta}-induced cEC apoptosis, barrier dysfunction, and angiogenic impairment. This study reveals specific mechanisms through which amyloidosis and Hhcy jointly operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in comorbid AD/CAA and Hhcy conditions.

neuroscience↗

bioRxiv2022

FDA-approved carbonic anhydrase inhibitors reduce Amyloid beta pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness

Alzheimers disease (AD) is a devastating neurodegenerative disorder with no effective cure. Cerebrovascular and neurovascular pathology are early and causal hallmarks of AD, where cerebral amyloid angiopathy (CAA), the deposition of amyloid {beta} (A{beta}) at the cerebral vasculature, is present in about 90% of cases. Our previous work has uncovered the protective effect of carbonic anhydrase (CA) inhibition against A{beta}-mediated mitochondrial dysfunction, production of reactive oxygen species (ROS) and apoptosis in vascular, glial and neuronal cells in culture. Here, we tested for the first time in a transgenic model of AD and cerebrovascular amyloidosis, the TgSwDI mice, a therapeutic regimen employing the FDA-approved CA inhibitors (CAIs), methazolamide (MTZ) and acetazolamide (ATZ). These drugs are used in humans for glaucoma, high altitude sickness, and other disorders, and can cross the blood-brain barrier. We found that both CAIs were non- toxic, significantly reduced cerebral amyloidosis, vascular, microglial and astrocytic A{beta} accumulation, and ameliorated cognition. MTZ and ATZ treatment prevented caspase-3 activation in endothelial cells, microglia and astrocytes, reverted capillary constriction and microhemorrhages, reduced gliosis, and induced glial pro-clearance pathways, which are likely responsible for the reduction of A{beta} deposition. Notably, we unveiled a critical new druggable target, revealing that the mitochondrial isozyme CA-VB is specifically upregulated in TgSwDI mouse brains, as well as in human brains of CAA and AD (with CAA) patients. Importantly, A{beta} challenge induced CA-VB overexpression in human cerebral endothelial cells, and CA-VB silencing, mimicking CAIs effects, reduced A{beta}-mediated endothelial apoptosis. This work paves the way for the application of CAIs in clinical trials for AD and CAA and uncovers CA-VB as a mediator of cerebral amyloid toxicity.

neuroscience↗