A5076733373- Alzheimer's disease research and treatments
- Neuroscience and Neuropharmacology Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Prion Diseases and Protein Misfolding
- Amyotrophic Lateral Sclerosis Research
- RNA Interference and Gene Delivery
- Parkinson's Disease Mechanisms and Treatments
- Neurogenetic and Muscular Disorders Research
- Cholinesterase and Neurodegenerative Diseases
- RNA Research and Splicing
- Trace Elements in Health
- DNA and Nucleic Acid Chemistry
- Lysosomal Storage Disorders Research
- Neurological diseases and metabolism
- Advanced biosensing and bioanalysis techniques
- RNA regulation and disease
- Cellular transport and secretion
- CRISPR and Genetic Engineering
- Chromosomal and Genetic Variations
- Nuclear Structure and Function
- Calpain Protease Function and Regulation
- Pluripotent Stem Cells Research
- Dementia and Cognitive Impairment Research
- Memory and Neural Mechanisms
- Neurogenesis and neuroplasticity mechanisms
Denali Therapeutics (United States)
2020-2024
Kaiser Permanente South San Francisco Medical Center
2023
Harvard University
2015-2021
Massachusetts General Hospital
2015-2021
MaineGeneral Medical Center
2015-2021
Washington University in St. Louis
2012-2017
Hope Center for Neurological Disorders
2013-2017
Central Michigan University
2011
Van Andel Institute
2009
Joint Research Centre
1993
Recent experimental evidence suggests that transcellular propagation of fibrillar protein aggregates drives the progression neurodegenerative diseases in a prion-like manner. This phenomenon is now well described cell and animal models involves release into extracellular space. Free then enter neighboring cells to seed further fibrillization. The mechanism by which aggregated proteins such as tau α-synuclein bind trigger intracellular fibril formation unknown. Prior work indicates prion...
Antisense oligonucleotides that reduce tau prevent neuronal loss and reverse deposition seeding in a mouse model of tauopathy.
Abstract Tau pathology is known to spread in a hierarchical pattern Alzheimer’s disease (AD) brain during progression, likely by trans-synaptic tau transfer between neurons. However, the species involved inter-neuron propagation remains unclear. To identify responsible for propagation, we examined uptake and properties of different derived from postmortem cortical extracts interstitial fluid tau-transgenic mice, as well human AD cortices. Here show that PBS-soluble phosphorylated...
Tau, a microtubule-associated protein, is implicated in the pathogenesis of Alzheimer's Disease (AD) regard to both neurofibrillary tangle formation and neuronal network hyperexcitability. The genetic ablation tau substantially reduces hyperexcitability AD mouse lines, induced seizure models, vivo models epilepsy. These data demonstrate that an important regulator excitability. However, developmental compensation knock-out line may account for protective effect against seizures. To test...
Engineering human IgG1 Fc binding to a brain endothelial cell–enriched receptor allows enhanced exposure of biotherapeutics in multiple species.
Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed hyperphosphorylated tau aggregates and extracellular amyloid-beta plaques. The spread pathology through brain classified Braak stages thought to correlate progression AD. Several in vitro vivo studies have examined moving from one neuron next, suggesting a "prion-like" may be an underlying cause staging Using HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as highly sensitive...
Misfolding of microtubule-associated protein tau (MAPT) within neurons into neurofibrillary tangles is an important pathological feature Alzheimer's disease (AD). Tau pathology correlates with cognitive decline in AD and follows a stereotypical anatomical course; several recent studies indicate that spreads inter-neuronally via misfolded "seeds." Previous research has focused on as the source these seeds. However, well data contained herein suggest microglia, resident immune cells central...
Objective Recent studies have shown that positron emission tomography (PET) tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF)-tau pathology in Alzheimer's brains. However, the ability of this ligand to bind tau lesions other tauopathies remains controversial. Our goal was examine correlation vivo and postmortem patterns three autopsy-confirmed non-Alzheimer tauopathy cases. Methods We quantified retention [F-18]-AV-1451 performed autoradiography, [H-3]-AV-1451...
Genetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression mutated transgenes have yielded key insights mechanisms disease, those are subject to artifacts, including random genetic integration transgene, ectopic expression and non-physiological protein levels. The engineering novel using knock-in approaches addresses some limitations. With...
Antisense oligonucleotides (ASOs) are promising therapeutics for treating various neurological disorders. However, ASOs unable to readily cross the mammalian blood-brain barrier (BBB) and therefore need be delivered intrathecally central nervous system (CNS). Here, we engineered a human transferrin receptor 1 (TfR1) binding molecule, oligonucleotide transport vehicle (OTV), tool ASO across BBB in TfR knockin (TfR mu/hu KI) mice nonhuman primates. Intravenous injection systemic delivery of...
Due to an inability cross the blood brain barrier, certain drugs need be directly delivered into central nervous system (CNS). Our lab focuses specifically on antisense oligonucleotides (ASOs), though techniques shown in video here can also used deliver a plethora of other CNS. Antisense (ASOs) have capability knockdown sequence-specific targets (1) as well shift isoform ratios specific genes (2). To achieve widespread gene or splicing CNS mice, ASOs using two separate routes administration,...
Local replication doubles the number of tau aggregate in Alzheimer’s disease only once every 5 years, limiting overall rate.
Cerebrospinal fluid (CSF) tau is an excellent surrogate marker for assessing neuropathological changes that occur in Alzheimer's disease (AD) patients. However, whether the elevated AD CSF just a of neurodegeneration or, fact, part process uncertain. Moreover, it unknown how relates to recently described soluble high-molecular-weight (HMW) species found postmortem brain and can be taken up by neurons seed aggregates.We have examined seeding uptake properties extracellular from various...
Several studies have now supported the use of a tau lowering agent as possible therapy in treatment tauopathy disorders, including Alzheimer's disease. In human disease, however, concurrent amyloid-β deposition appears to synergize and accelerate pathological changes. Thus far, reduction strategies that been tested vivo examined setting pathology without confounding deposition. To determine whether reducing total expression transgenic model where there is plaque formation can still reduce...
Transposable elements comprise almost half of the mammalian genome. A growing body evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, activation is neurotoxic. Recent studies have identified links between pathogenic forms tau, a protein accumulates in Alzheimer's disease related "tauopathies," element-induced neurotoxicity. Starting with transcriptomic analyses, we find age- tau-induced occurs mouse brain. Among are activated at...