A5011401538- Alzheimer's disease research and treatments
- Virus-based gene therapy research
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA Interference and Gene Delivery
- Nuclear Receptors and Signaling
- Neuroscience and Neuropharmacology Research
- CRISPR and Genetic Engineering
- Cholesterol and Lipid Metabolism
- 14-3-3 protein interactions
- Cerebrospinal fluid and hydrocephalus
- Bioinformatics and Genomic Networks
- Signaling Pathways in Disease
- Hormonal Regulation and Hypertension
- RNA regulation and disease
- interferon and immune responses
- Extracellular vesicles in disease
- Computational Drug Discovery Methods
- Barrier Structure and Function Studies
- Nicotinic Acetylcholine Receptors Study
- Dementia and Cognitive Impairment Research
- Neurological Disease Mechanisms and Treatments
- Viral Infections and Immunology Research
- Cancer Research and Treatments
- Prion Diseases and Protein Misfolding
- Cholinesterase and Neurodegenerative Diseases
Novartis (United States)
2021-2025
Massachusetts General Hospital
2013-2023
Harvard University
2013-2023
MaineGeneral Medical Center
2013-2023
Harvard NeuroDiscovery Center
2016-2021
Inserm
2009-2015
Institute for Neurodegenerative Disorders
2015
Université Paris-Sud
2015
Délégation Paris 5
2009
Université Paris Cité
2009
Gene expression profiles of more than 10,000 individual microglial cells isolated from cortex and hippocampus male female App
Amyloid beta (Abeta)-containing plaques are surrounded by dystrophic neurites in the Alzheimer's disease (AD) brain, but whether and how induce these neuritic abnormalities remain unknown. We tested hypothesis that soluble oligomeric assemblies of Abeta, which surround plaques, calcium-mediated secondary cascades lead to changes local neurites. show Abeta oligomers activation calcium-dependent phosphatase calcineurin (CaN) (PP2B), turn activates transcriptional factor nuclear activated T...
Abstract Mitochondria contribute to shape intraneuronal Ca 2+ signals. Excessive taken up by mitochondria could lead cell death. Amyloid beta (Aβ) causes cytosolic overload, but the effects of Aβ on mitochondrial levels in Alzheimer’s disease (AD) remain unclear. Using a ratiometric indicator targeted neuronal and intravital multiphoton microscopy, we find increased associated with plaque deposition death transgenic mouse model cerebral β-amyloidosis. Naturally secreted soluble applied onto...
Abnormalities in neuronal cholesterol homeostasis have been suspected or observed several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has not demonstrated whether an increased abundance of neurons vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology inhibit the expression 24-hydroxylase, encoded by Cyp46a1 gene, hippocampus normal mice. Cholesterol 24-hydroxylase controls...
Abstract Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, periphery largely liver. ApoE has been shown to impact integrity of blood–brain barrier, and, humans, APOE4 allele gene reported lead leaky barrier. We used specific knock-in mice expressing each common (human) alleles, longitudinal multiphoton intravital microscopy, directly monitor various isoforms on barrier integrity. found that humanized APOE4, but not APOE2 or APOE3,...
The development of Alzheimer's disease (AD) is closely connected with cholesterol metabolism. Cholesterol increases the production and deposition amyloid-beta (Abeta) peptides that result in formation amyloid plaques, a hallmark pathology. In brain, synthesized situ but cannot be degraded nor cross blood-brain barrier. major exportable form brain 24S-hydroxycholesterol, an oxysterol generated by neuronal 24-hydroxylase encoded CYP46A1 gene. We report injection adeno-associated vector (AAV)...
Introduction of different APOE isoforms modulates Aβ peptide aggregation and neurotoxicity after amyloid deposition in mouse brain.
We observed enhanced tau spreading in the aging mouse brain and misfolding regions vulnerable Alzheimer’s disease.
Amyloid-β oligomers (oAβ) are thought to mediate neurotoxicity in Alzheimer's disease (AD), and previous studies AD transgenic mice suggest that calcium dysregulation may contribute these pathological effects. Even though mouse models remain a valuable resource investigate amyloid neurotoxicity, the concomitant presence of soluble Aβ species, fibrillar Aβ, fragments precursor protein (APP) complicate interpretation phenotypes. To explore specific contribution oligomeric dyshomeostasis...
The apolipoprotein E E4 allele of the APOE gene is strongest genetic factor for late-onset Alzheimer disease (LOAD). There compelling evidence that apoE influences (AD) in large part by affecting amyloid β (Aβ) aggregation and clearance; however, molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti–human antibodies can decrease Aβ pathology mice producing both human apoE4, investigated effects. We utilized APPPS1-21 crossed to apoE4-knockin...
Adeno-associated virus (AAV) capsid libraries have generated improved transgene delivery vectors. We designed an AAV library construct, iTransduce, that combines a peptide on the AAV9 with Cre cassette to enable sensitive detection of expression. After only two selection rounds delivered intravenously in transgenic mice carrying Cre-inducible fluorescent protein, we flow sorted cells from brain, and DNA sequencing revealed dominant capsids. One capsids, termed AAV-F, mediated expression...
Abstract Developing therapies for central nervous system ( CNS ) diseases is exceedingly difficult because of the blood–brain barrier BBB ). Notably, emerging technologies may provide promising new options treatment disorders. Adeno‐associated virus serotype 9 AAV 9) has been shown to transduce cells in following intravascular administration rodents, cats, pigs, and non‐human primates. These results suggest that capable crossing . However, mechanisms govern transendothelial trafficking at...
Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) clearance and aggregation, which likely contributes in large part to its role AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aβ plaque load when given APPswe/PS1ΔE9 (APP/PS1) mice starting before of deposition. To determine whether anti-apoE HJ6.3 affects plaques, neuronal network function, behavior...
Abstract Neuroinflammation is a key contributor to the pathology of Alzheimer’s disease (AD). CD33 (Siglec-3) transmembrane sialic acid-binding receptor on surface microglial cells. upregulated cells from post-mortem AD patient brains, and high levels inhibit uptake clearance amyloid beta (Aβ) in cell cultures. Furthermore, knockout reduces plaque burden mouse models AD. Here, we tested whether gene therapy strategy reduce microglia could decrease Aβ load. Intracerebroventricular injection...
Amyloid β (Aβ) peptides, the main pathological species associated with Alzheimer's disease (AD), disturb intracellular calcium homeostasis, which in turn activates calcium-dependent phosphatase calcineurin (CaN). CaN activation induced by Aβ leads to morphological changes neurons, and overexpression of constitutively active is sufficient generate a similar phenotype, even without Aβ. Here, we tested hypothesis that mediates neurodegenerative effects via nuclear transcription factor activated...
Amyloid-beta protein (Aβ) deposition is a pathological hallmark of Alzheimer's disease (AD). Aβ triggers both pro-neuroinflammatory microglial activation and neurofibrillary tangle formation. Cromolyn sodium an asthma therapeutic agent previously shown to reduce levels in transgenic AD mouse brains after one-week treatment. Here, we further explored these effects as well the mechanism action cromolyn, alone, combination with ibuprofen APPSwedish-expressing Tg2576 mice. Mice were treated for...
Adeno-associated viral vectors (AAVs) have demonstrated potential in applications for neurologic disorders, and the discovery that some AAVs can cross blood-brain barrier (BBB) after intravenous injection has further expanded these opportunities non-invasive brain delivery. Anc80L65, a novel AAV capsid designed from silico reconstruction of evolutionary lineage, previously robust transduction capabilities local delivery various tissues such as liver, retina, or cochlea, compared with...
Interfering with the assembly of Amyloid β (Aβ) peptides from monomer to oligomeric species and fibrils or promoting their clearance brain are targets anti-Aβ-directed therapies in Alzheimer disease. Here we demonstrate that cromolyn sodium (disodium cromoglycate), a Food Drug Administration-approved drug already use for treatment asthma, efficiently inhibits aggregation Aβ monomers into higher-order oligomers vitro without affecting production. In vivo, levels soluble decreased by over 50%...
Hepatotoxicity associated with intravenous/intrathecal adeno-associated virus (AAV) gene therapy has been observed in preclinical species and patients. In nonhuman primates, hepatotoxicity following self-complementary AAV9 administration varies from asymptomatic transaminase elevation minimal to mild microscopic changes symptomatic elevations of liver function thromboinflammatory markers consistent marked hepatocellular necrosis deteriorating clinical condition. These transient acute injury...