Basic Science and Pathogenesis.

Background: By 2050 the number of Alzheimer's Disease (AD) patients is projected to exceed 150 million worldwide. AD is an incurable, insufficiently understood, and devastating neurodegenerative disease, with high patient heterogeneity in terms of progression, clinical manifestation (including neuropsychiatric symptoms, NPS) and, importantly, responsiveness to treatment options.[1] In the last 20 years, 98% of clinical trials for AD have failed, highlighting the urgent need to drastically change pre-clinical research to develop better predictors of drug safety and effectiveness.

Pharmacokinetics and biodistribution of extracellular vesicles administered intravenously and intranasally to .

Extracellular vesicles (EVs) have potential in disease treatment since they can be loaded with therapeutic molecules and engineered for retention by specific tissues. However, questions remain on optimal dosing, administration, and pharmacokinetics. Previous studies have addressed biodistribution and pharmacokinetics in rodents, but little evidence is available for larger animals.

Human Pluripotent Stem Cells as In Vitro Models of Neurodegenerative Diseases.

My main research focused in the last years has been the reprogramming of differentiated cell types, such as human fibroblasts, into pluripotent stem cells called induced pluripotent stem cells (iPSCs) and the application of this technology to studies of the nervous system and the diseases that affect it. We have been working on the generation of iPSC lines from Alzheimer's disease (AD) patients using recent developments in reprogramming strategies such as non-integrating episomal vectors to produce virus-free, clinical safe hiPSC. Our study shows that neurons differentiated from these cells display important disease properties and, thus, have the potential to serve as cellular models to explore various aspects of Alzheimer's pathogenesis.

Conditional gene knockout and reconstitution in human iPSCs with an inducible Cas9 system.

Precise genome editing in human induced pluripotent stem cells (iPSCs) significantly enhances our capability to use human iPSCs for disease modeling, drug testing and screening as well as investigation of human cell biology. In this study, we seek to achieve conditional expression of the CD55 gene in order to interrogate its functions. We used two human iPSC lines that have unique genotypes, and constructed an inducible Cas9 gene expression system that is integrated at the AAVS1 safe harbor site in the human genome.

Extracellular Vesicle-Associated Aβ Mediates Trans-Neuronal Bioenergetic and Ca-Handling Deficits in Alzheimer's Disease Models.

Alzheimer's Disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs) are small 50-150 nanometer membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient CSF and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity.