A5090113190- Alzheimer's disease research and treatments
- Ferroptosis and cancer prognosis
- Mitochondrial Function and Pathology
- Tryptophan and brain disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Metabolomics and Mass Spectrometry Studies
- Medicinal Plants and Bioactive Compounds
- Cancer-related molecular mechanisms research
- Diet and metabolism studies
- Neuroscience and Neuropharmacology Research
- Genetics, Aging, and Longevity in Model Organisms
- Lysosomal Storage Disorders Research
- Nuclear Receptors and Signaling
- Cholinesterase and Neurodegenerative Diseases
- Bipolar Disorder and Treatment
- Drug Transport and Resistance Mechanisms
- Wnt/β-catenin signaling in development and cancer
- Advanced Glycation End Products research
- 14-3-3 protein interactions
- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- Epigenetics and DNA Methylation
- Cholesterol and Lipid Metabolism
- ATP Synthase and ATPases Research
- Endoplasmic Reticulum Stress and Disease
Salk Institute for Biological Studies
2016-2025
King's College London
2006-2011
Osaka University
2009-2011
Instituto Gulbenkian de Ciência
2007
Summary Alzheimer's disease ( AD ) is the most common type of dementia. It only one top ten causes death in USA for which prevention strategies have not been developed. Although has traditionally associated with deposition amyloid β plaques and tau tangles, it becoming increasingly clear that involves disruptions multiple cellular systems. Therefore, unlikely hitting a single target will result significant benefits to patients . An alternative approach identify molecules biological...
Summary Aging is a major driving force underlying dementia, such as that caused by Alzheimer's disease ( AD ). While the idea of targeting aging therapeutic strategy not new, it remains unclear how closely and age‐associated diseases are coupled at molecular level. Here, we discover novel link between dementia through identification target for drug candidate J147. J147 was developed using series phenotypic screening assays mimicking toxicities associated with brain. We have previously...
Because old age is the greatest risk factor for dementia, a successful therapy will require an understanding of physiological changes that occur in brain with aging. Here, two structurally distinct Alzheimer's disease (AD) drug candidates, CMS121 and J147, were used to identify unique molecular pathway shared between aging AD. J147 reduced cognitive decline as well metabolic transcriptional markers when administered rapidly SAMP8 mice. Both compounds preserved mitochondrial homeostasis by...
Alzheimer's disease (AD) is rarely addressed in the context of aging even though there an overlap pathology. We previously used a phenotypic screening platform based on old age–associated brain toxicities to identify flavonol fisetin as potential therapeutic for AD and other age-related neurodegenerative diseases. Based earlier results with transgenic mice, we hypothesized that would be effective against cognitive dysfunction rapidly senescence-accelerated prone 8 (SAMP8) model sporadic...
The oxidative degradation of lipids has been shown to be implicated in the progression several neurodegenerative diseases and modulating lipid peroxidation may efficacious for treating Alzheimer's disease (AD). This hypothesis is strengthened by recent findings suggesting that oxytosis/ferroptosis, a cell death process characterized increased peroxidation, plays an important role AD-related toxicities. CMS121 small molecule developed against these aspects neurodegeneration. Here we show...
Abstract Amyloid beta (Aβ) accumulates within neurons in the brains of early stage Alzheimer’s disease (AD) patients. However, mechanism underlying its toxicity remains unclear. Here, a triple omics approach was used to integrate transcriptomic, proteomic, and metabolomic data collected from nerve cell model toxic intracellular aggregation Aβ. It found that Aβ induces profound changes landscape cells are associated with pro-inflammatory, metabolic reprogramming predisposes die via...
Aging | doi:10.18632/aging.100838. Antonio Currais, Joshua Goldberg, Catherine Farrokhi, Max Chang, Marguerite Prior, Richard Dargusch, Daniel Daugherty, Aaron Armando, Oswald Quehenberger, Pamela Maher, David Schubert
The beta amyloid (Aβ) and other aggregating proteins in the brain increase with age are frequently found within neurons. mechanistic relationship between intracellular amyloid, aging neurodegeneration is not, however, well understood. We use a proteotoxicity model based upon inducible expression of Aβ human central nervous system nerve cell line to characterize distinct form death caused by Aβ. It shown that initiates toxic inflammatory response leading cell's demise. induces multiple...
Alzheimer's disease (AD) is the most frequent age-associated dementia with no treatments that can prevent or slow its progression. Since age by far major risk factor for AD, there a strong rationale an alternative approach to drug discovery based upon biology of aging. Phenotypic screening assays reflect multiple, neurotoxicity pathways rather than single molecular targets identify compounds have therapeutic efficacy targeting aspects aging contribute AD pathology. And, while suitability any...
The global increase in the aging population has led to a rise many age-related diseases with continuing unmet therapeutic needs. Research into molecular mechanisms underlying both and neurodegeneration identified promising targets, such as oxytosis/ferroptosis cell death pathway, which mitochondrial dysfunction plays critical role. This study focused on sterubin fisetin, two flavonoids from natural pharmacopeia previously strong inhibitors of pathway. Here, we investigated effects compounds...
Mounting evidence supports a link between diabetes, cognitive dysfunction, and aging. However, the physiological mechanisms by which diabetes impacts brain function cognition are not fully understood. To determine how contributes to dysfunction age-associated pathology, we used streptozotocin induce type 1 (T1D) in senescence-accelerated prone 8 (SAMP8) senescence-resistant (SAMR1) mice. Contextual fear conditioning demonstrated that T1D resulted development of deficits SAMR1 mice similar...
AbstractPresenilin-1 (PS1) is a component of the β-catenin degradation machinery, and PS1 mutations linked to familial Alzheimer's disease (FAD) represent loss this function, leading, in non-neuronal cells, accumulation cyclin D1, aberrant cell cycle activation hyperproliferation. In post-mitotic neurons, thought be abortive initiate apoptosis, thus contributing AD pathogenesis. Consequently, we tested here hypothesis that, FAD brain, D1 may occur lead neuronal apoptosis secondary an entry...
Abstract Mutations in the coding sequence of methyl‐CpG‐binding protein 2 gene ( MECP2 ), which cause Rett syndrome (RTT), have been found male and female autistic subjects without, however, a causal relation having unequivocally established. In this study, was scanned Portuguese population, hypothesizing that phenotypic spectrum mutations extends beyond traditional diagnosis RTT X‐linked mental retardation, leading to non‐lethal phenotype patients. The region, exon–intron boundaries, whole...
Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy worldwide, presenting clinically as muscle weakness that progresses to impaired ambulation or quadriplegia with age. CMT1A, subtype, caused by a duplication in PMP22, encoding an essential membrane protein for Schwann cell myelin integrity. While mechanisms of neurodegeneration CMT1A are poorly understood, excessive oxidative stress, particularly lipid peroxidation, known pathological feature, and...