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Background: While the formation of β-amyloid plaques and neurofibrillary "tau" tangles are considered hallmarks of AD pathology, therapeutic targeting of these pathways has been unsuccessful, highlighting the necessity to define the underlying molecular mechanisms driving AD progression. Previous studies from our lab demonstrated that mitochondrial calcium (Ca) overload through neuronal ablation of the mitochondrial Na/Ca exchanger (NCLX) is sufficient to trigger 'AD-like' pathology, including mitochondrial dysfunction, amyloid deposition and tau pathology, and cognitive decline. In addition, we found significant proteomic remodeling of components of the mitochondrial calcium uniporter channel (mtCU), the primary mediator of Ca uptake, in frontal cortex samples isolated post-mortem from patients diagnosed with non-familial/sporadic AD.
View Article and Find Full Text PDFDeveloping Topics.
Alzheimers Dement
December 2024
University of Miami Miller School of Medicine, Center for Therapeutic Innovation, Miami, FL, USA.
Background: Rapamycin is currently in clinical trials for AD, yet numerous studies have suggested that rapamycin inhibits mTORC2 as well as mTORC1, which could be detrimental for AD pathology. Brain insulin resistance is a known aspect of AD pathology and mTORC2 inhibition reduces AKT phosphorylation, which is a main mediator of cellular insulin signaling, perpetuating insulin resistance and further worsening brain glucose metabolism. Here, we show that rapamycin prevents insulin-induced AKT phosphorylation in human neurons and explore the differential effects of mTORC1 and mTORC2 on neuronal insulin sensitivity.
View Article and Find Full Text PDFAAVR Expression is Essential for AAV Vector Transduction in Sensory Hair Cells.
Adv Sci (Weinh)
January 2025
Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China.
Adeno-associated virus (AAV) vectors are a leading platform for gene therapy. Recently, AAV-mediated gene therapy in the inner ear has progressed from laboratory use to clinical trials, but the lower transduction rates in outer hair cells (OHCs) in the organ of Corti and in vestibular hair cells in adult mice still pose a challenge. OHCs are particularly vulnerable to inner ear insults.
View Article and Find Full Text PDFLipid Nanoparticles Enable Efficient In Vivo DNA Knock-In via HITI-Mediated Genome Editing.
Biomolecules
December 2024
Graduate School of Engineering Science, Osaka University, Toyonaka 560-8531, Osaka, Japan.
In vivo genome editing holds great therapeutic potential for treating monogenic diseases by enabling precise gene correction or addition. However, improving the efficiency of delivery systems remains a key challenge. In this study, we investigated the use of lipid nanoparticles (LNPs) for in vivo knock-in of ectopic DNA.
View Article and Find Full Text PDFBackground: Long QT Syndrome Type-2 (LQT2) is due to loss-of-function variants. encodes K 11.1 that forms a delayed-rectifier potassium channel in the brain and heart.
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