31 research outputs found
Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing.
Neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Huntington's disease manifest with the neuronal accumulation of toxic proteins. Since autophagy upregulation enhances the clearance of such proteins and ameliorates their toxicities in animal models, we and others have sought to re-position/re-profile existing compounds used in humans to identify those that may induce autophagy in the brain. A key challenge with this approach is to assess if any hits identified can induce neuronal autophagy at concentrations that would be seen in humans taking the drug for its conventional indication. Here we report that felodipine, an L-type calcium channel blocker and anti-hypertensive drug, induces autophagy and clears diverse aggregate-prone, neurodegenerative disease-associated proteins. Felodipine can clear mutant α-synuclein in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug. This is associated with neuroprotection in mice, suggesting the promise of this compound for use in neurodegeneration
Basic to translational research in dementia: meeting report from the Alzheimer’s Research UK Conference 2014
The secretases that cleave angiotensin converting enzyme and the amyloid precursor protein are distinct from tumour necrosis factor-α convertase
AbstractAngiotensin converting enzyme (ACE) and the Alzheimer's amyloid precursor protein are cleaved from the membrane by zinc metalloproteinases termed ACE secretase and α-secretase, respectively. Tumour necrosis factor-α (TNF-α) convertase (ADAM 17) is a recently identified member of the adamalysin family of mammalian zinc metalloproteinases that is involved in the production of TNF-α and possibly in the cleavage of other membrane proteins. Using two different cell-free assays we were unable to detect significant cleavage and secretion of ACE by TNF-α convertase. In addition, there was a different effect of three hydroxamic acid-based inhibitors (batimastat, compound 1 and compound 4) towards TNF-α convertase as compared to ACE secretase and α-secretase. Thus TNF-α convertase would appear to be distinct from, but possibly related to, the secretases that cleave ACE and the amyloid precursor protein
Epitope-specific antibody-induced cleavage of angiotensin-converting enzyme from the cell surface
Characterization of Detergent-Insoluble Complexes Containing the Familial Alzheimer's Disease-Associated Presenilins.
Many cases of early-onset familial Alzheimer’s disease have been linked to mutations within two genes encoding the proteins presenilin-1 and presenilin-2. The presenilins are 48-56-kDa proteins that can be proteolytically cleaved to generate an N-terminal fragment (25-35 kDa) and a C-terminal fragment (17-20 kDa). The N- and C-terminal fragments of presenilin-1, but not full-length presenilin-1, were readily detected in both human and mouse cerebral cortex and in neuronal and glioma cell lines. In contrast, presenilin-2 was detected almost exclusively in cerebral cortex as the full-length molecule with a molecular mass of 56 kDa. The association of the presenilins with detergent-insoluble, low-density membrane microdomains, following the isolation of these structures from cerebral cortex by solubilization in Triton X-100 and subsequent sucrose density gradient centrifugation, was also examined. A minor fraction (10%) of both the N- and C-terminal fragments of presenilin-1 was associated with the detergent-insoluble, low-density membrane microdomains, whereas a considerably larger proportion of full-length presenilin-2 was present in the same membrane microdomains. In addition, a significant proportion of full-length presenilin-2 was present in a high-density, detergent-insoluble cytoskeletal pellet enriched in β-actin. The presence of the presenilins in detergent-insoluble, low-density membrane microdomains indicates a possible role for these specialized regions of the membrane in the lateral separation of Alzheimer’s disease-associated proteins within the lipid bilayer and/or in the distinct functions of these proteins
Report from the Alzheimer's Research UK Conference 2015
Abstract On 10-11 March 2015 University College London hosted the annual Alzheimer's Research UK Conference. This report provides an overview of the presentations and discussions that took place