-
J. Pickett, A.K. Mudher,
C. Holmes,
C. Katona,
E.K. Perry,
I. Testad,
J. Hagan,
J. Corcoran,
N. Bailey,
P.G. Kehoe,
P.A. Passmore,
S.B. Dunnett,
A. Burns
[show abstract]
[hide abstract]
ABSTRACT: Alzheimer's disease is the most common cause of dementia, and is expected to affect 115 million people worldwide by 2025. Existing treatments provide symptomatic benefit for up to 12 months but there are no licensed disease-modifying treatments and few ongoing clinical trials. The substantial economic and personal cost associated with AD highlights the urgency of developing new, effective, disease-modifying treatments. Drug repositioning is an attractive strategy for identifying new therapies for AD, with a substantial body of pre-clinical work indicating that drugs licensed for other indications have the potentially beneficial effects on Alzheimer pathology. For some drugs, the evidence is also supported by favourable epidemiological data or preliminary clinical trials. This review presents a systematic evaluation of drug candidates based on a systematic review of published literature and a formal expert consensus by academics, industry experts and people living with Alzheimer's disease. This evidence
Nature Biotechnology 01/2012; submitted�
�. · 29.50 Impact Factor
-
R Killick,
C C Pollard,
A A Asuni, A K Mudher,
J C Richardson,
H T Rupniak,
P W Sheppard,
I M Varndell,
J P Brion,
A I Levey,
O A Levy,
M Vestling,
R Cowburn,
S Lovestone,
B H Anderton
[show abstract]
[hide abstract]
ABSTRACT: Presenilin 1 (PS1) regulates beta-catenin stability; however, published data regarding the direction of the effect are contradictory. We examined the effects of wild-type and mutant forms of PS1 on the membrane, cytoplasmic, nuclear, and signaling pools of endogenous and exogenous beta-catenin by immunofluorescence microscopy, subcellular fractionation, and in a transcription assay. We found that PS1 destabilizes the cytoplasmic and nuclear pools of beta-catenin when stabilized by Wnt or Dvl but not when stabilized at lower levels of the Wnt pathway. The PS1 mutants examined were less able to reduce the stability of beta-catenin. PS1 also inhibited the transcriptional activity of endogenous beta-catenin, and the PS1 mutants were again less inhibitory at the level of Dvl but showed a different pattern of inhibition toward transcription below Dvl. The transcriptional activity of exogenously expressed wild-type beta-catenin and two mutants, DeltaN89beta-catenin and DeltaSTbeta-catenin, were also inhibited by wild-type and mutant PS1. We conclude that PS1 negatively regulates the stability and transcriptional activity of beta-catenin at different levels in the Wnt pathway, that the effect on transcriptional activity appears to be independent of the GSK-3beta mediated degradation of beta-catenin, and that mutations in PS1 differentially affect the stability and transcriptional activity of beta-catenin.
Journal of Biological Chemistry 01/2002; 276(51):48554-61. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hyperphosphorylated tau is a pathological hallmark of Alzheimer's disease, but the mechanisms that lead to its formation are poorly understood. To investigate what effect deafferentation of the hippocampus has on the phosphorylation state of tau, we lesioned the entorhinal cortex in rats and looked for hyperphosphorylated tau in the hippocampus at various days post lesioning. After 7 and 21 days, small AT8-positive 'granules' appeared in the molecular layer of the dentate gyrus on the lesioned side. No such staining was seen in the animals injected with saline. This study shows that deafferentation leads to induction of hyperphosphorylated tau. The AT8 positive 'granules' seen resemble the argyrophilic grains that characterize Argyrophilic Grain disease suggesting that lesioning the perforant pathway may serve as a useful model for inducing argyrophilic grains in vivo.
Neuroscience Letters 04/2001; 301(1):5-8. · 2.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although hyperphosphorylated tau is an established feature of Alzheimer's Disease, its role in the disease process is poorly understood, partly because of lack of suitable animal models. We describe the use of living slices of rat hippocampal formation to study tau phosphorylation. Using the AT8 antibody in an ELISA, phosphorylated tau was detected in freshly frozen slices and it increased significantly in slices that were incubated in an electrophysiological recording chamber; the amount detected was greatest when the homogenisation buffer contained phosphatase and kinase inhibitors. The phosphorylated tau content of the slices increased significantly after exposure to the phosphatase 1 and 2A inhibitor okadaic acid (OA) - 1.5 microM. Electrophysiological recordings confirmed that slices were alive and that OA had no acute toxic effect. In control slices phosphorylated tau, detected immunohistochemically, was mainly in the somatodendritic compartment of neurones; in OA treated slices, there was an apparent decrease in somatodendritic AT8 staining and an increase in neuropil staining. Our system enables the induction of hyperphosphorylated tau within living slices, in an experimental environment that can be used to study the biological consequences of such a change, and may therefore help further our understanding of the significance of hyperphosphorylated tau in Alzheimer's Disease.
Journal of Neuroscience Methods 05/1999; 88(1):15-25. · 1.98 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The pathological hallmarks of Alzheimer's disease include neurofibrillary tangles, neuropil threads and neuritic plaques. Neurofibrillary tangles and neuropil threads are comprised of paired helical filaments which are themselves composed of a hyperphosphorylated form of the microtubule-associated protein tau. Neuritic plaques are extracellular deposits of aggregated beta amyloid associated with neurites containing hyperphosphorylated tau. The mechanisms by which the neurofibrillary tangles and neuritic plaques develop in Alzhemier's disease are not clear but it is hypothesized that sulphated glycosaminoglycans are important in their formation. This impression is based on the finding that the glycosaminoglycan, heparan sulphate, is found associated with neurofibrillary tangles, neuritic plaques and neuropil threads while dermatan sulphate, chondroitin sulphate and keratan sulphate immunoreactivity is found around neuritic plaques in brains of Alzheimer's disease patients. Furthermore, in vitro studies demonstrate that sulphated glycosaminoglycans such as heparan sulphate and the closely related molecule heparin interact with tau and potentiate its phosphorylation by a number of serine/threonine kinases, reduce its ability to bind to microtubules and induce paired helical filament formation, all properties associated with tau isolated from Alzheimer's disease brain. Thus, we were interested to learn whether intracerebral injection of the sulphated glycosaminoglycan heparin would give rise to alterations in the cytoskeletal protein tau in the rat brain. Although no cytoskeletal changes were observed, to our considerable surprise we found that the intrahippocampal injection of heparin gave rise to seizures. We have investigated this unexpected effect further in vivo and by using in vitro electrophysiological techniques.
Neuroscience 04/1999; 89(2):329-33. · 3.38 Impact Factor
-
Neuroscience 09/1998; 85(4):1329-32. · 3.38 Impact Factor
