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A joint seminar from UK DRI at UCL & The Francis Crick Institute: Mark W. Albers
12 December 2019, 12:00 pm–1:00 pm
Event Information
Open to
- All
Organiser
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Katharine Buckle
Location
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Foyer Meeting Room 1Cruciform BuildingGower St, FitzroviaLondonWC1E 6BT
A Common Mechanism for inflammatory Neuronal Death in Alzheimer’s Disease and ALS: From Bench to Basket Clinical Trial
Abstract
Cytoplasmic inclusions of the TAR Binding Protein (TDP)-43 occur in nearly half of autopsy-proven cases of Alzheimer’s disease (AD), and their presence correlates with a faster cognitive decline. In this talk, I will present evidence that cytoplasmic double stranded RNAs (cdsRNA), an established trigger of type I interferon (IFN-I), are coincident with cytoplasmic TDP-43 inclusions in AD. We find a strong association with interferon induction in AD brains relative to aged controls with no or very minor AD pathology. In parallel studies, we find similar colocalization of cdsRNA and TDP-43 inclusions in ALS associated with C9ORF72 mutations, and can demonstrate that a component of cdsRNA is derived from the hexanucleotide expansion. We demonstrate that cdsRNA is sufficient to induce propagated neuroinflammation and neuronal death in a unique mouse model with restricted expression of cdsRNA in a single class of neurons. We can recapitulate neuronal death evoked by cdsRNA in an in vitro model of human neurons, oligodendrocytes, and astrocytes that lack microglia. Further, both drug screening and an orthogonal informatics approach using machine learning of gene expression profiles in AD brains implicate a set of FDA-approved drugs that rescue neuronal death in vitro and evoke gene expression profiles inversely correlate with tau progression. Together, these data are consistent with a subtype of sporadic Alzheimer’s disease and FTD/ALS characterized by enhanced IFN-I signaling in setting of cdsRNA and TDP-43 cytoplasmic inclusions, that offer an opportunity for a repositioning drug trial.
About the Speaker
Mark W. Albers, M.D., Ph.D.
at Massachusetts General Hospital and Laboratory of System Pharmacology, Harvard Medical School
Mark W. Albers is a neurologist specializing in memory and olfactory disorders. He earned a PhD in organic chemistry from Harvard University, working in the laboratory of Stuart Schreiber, and an MD degree from the H.S.T. program of Harvard Medical School and M.I.T. He was an internal medicine resident for two years at Massachusetts General Hospital and then trained in neurology at Mass General, and Brigham and Women’s Hospital, where he was one of the first chief residents for the Partners neurology residency program. He completed a postdoctoral fellowship in the laboratory of Richard Axel while he practiced neurology at the Neurological Institute, Columbia University.
In 2007, he returned to Mass General where he sees outpatients in the Memory Disorders Unit and attends on the inpatient neurologic wards. His clinical research is focused on developing sensitive probes of olfactory function as a biomarker for early neurodegenerative disease, including Alzheimer’s and TBI. His laboratory research focuses on elucidating the mechanisms of neurodegeneration, identifying novel drug targets that mediate neurodegeneration, and developing therapies to prevent neurodegeneration. He served as a member of the Translational Neuroscience committee of the American Academy of Neurology, is a faculty member of the Laboratory of Systems Pharmacology, and is the Assistant Director of the Massachusetts Center for Alzheimer’s Therapeutic Science.