Biology subjects

Vazquez-Torres, R.

Publications and source records attributed to Vazquez-Torres, R..

2 recordsLinked to original sources

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↗

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↗