Transcript GSK-3 In Alzheimer's Disease
GSK-3 In Alzheimer's Disease pathogenic kinase, biomarker and therapeutic target - bench to bedside in action
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Urgent need for translational success
700,000 people with dementia in the UK over a million with dementia by 2025 financial cost of dementia to the UK is over £17 billion a year
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Accelerating translation through an AHSC
•
An example of bench to bedside translation
– GSK-3 as a biomarker and a therapeutic target in AD – in vitro, cellular models, animal models – biomarker discovery and early clinical trials •
Translation in the context of collaborative organisations
– three Trusts, one university; many collaborations, numerous disconnects •
Accelerated translation
– facilitating research – incentivising rapid translation Page 3
Alzheimer’s pathology
Neurofibrillary tangles composed of aggregated, phosphorylated tau Page 4 Amyloid plaques composed of a core of aggregated A b derived from APP
Amyloid cascade hypothesis
Environment Page 5 Genes
GSK-3 alters tau phosphorylation
Tau – no GSK3 Page 6
In vitro
Hanger
et al Neurosci. Lett.
(1992)
147
, 58-62
In non-neuronal cells and neurons
Lovestone et al
Curr Biol
(1994);
4
:1077-1086 Lovestone et al
Neuroscience
(1996)
73
1145-1157
In transgenic mice
Brownlees
et al. Neuroreport
(1997)
8
, 3251-3255 Tau – with GSK3
Amyloid cascade hypothesis
Environment GSK-3 Page 7 Genes
A
b
increases GSK-3 activity in neurons
Takashima,A. et al. Neurosci. Res. 31 , 317-323 (1998)
A
b
neurotoxicity is decreased by GSK-3 inhibition
Alvarez,G. et al. FEBS Lett. 453 , 260-264 (1999)
Tau over-expression phenotype is GSK-3 dependent Motor neuron expression of
-
Tau
-
Tau + GSK-3
b Wild-type Tau transgenic Page 8 Mudher et al (2004)
9,
522 530 3 4 5 6 7 8 9 1011 1213 14151617 Days post occlusion
GSK-3 inhibition rescues phenotype
Untreated GSK-3 inhibitor Page 9
GSK-3 inhibition rescues phenotype
Untreated GSK-3 inhibitor Page 10
GSK-3 dependent, tau induced phenotype
GSK-3 regulates memory and plasticity
• • Increased expression of GSK3 in mouse brain: Increased tau phosphorylation Deficits in learning and memory – Lucas et al,
EMBO J.
2001;20:27-39 Page 11 170 160 150 140 130 120 110 100 90 80 70 GSK3 inhibited wt Tet/GSK3 -30 -20 -10 0 10 20 30 40 50
Time (mins)
60 70 80 90 100 110 120 Hooper et al
Eur J Neurosci
(2007);
25:
81-86.
GSK3 regulation ie diabetes Genes associated with GSK3 regulation Page 12 GSK-3
GSK-3 as a biomarker for AD Increase in GSK-3 protein in AD and in MCI in white blood cells
Hye,A. et al. Neurosci. Lett. 373 , 1-4 (2005) 180.00
160.00
140.00
120.00
100.00
80.00
60.00
40.00
20.00
0.00
Controls
GSK-3 beta
** AD ** MCI **P<0.01
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GSK-3 inhibition as a therapeutic strategy
• •
Lithium is an inhibitor of GSK-3 In neurons and at therapeutic doses
Phosphorylated tau (ie AD like) Non- phosphorylated tau (ie normal) Page 14 Lovestone et al
Biol Psychiatry
1999; 45:995-1003 Leroy et al.
FEBS Lett
2000; 465:34-38
GSK-3 inhibition as a therapeutic strategy
•
Lithium is a safe and feasible treatment in AD
–One year, MRC sponsored trial –Macdonald et al.
Int J Geriatr Psychiatry
2008; 23:704-711.
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Lithium trials underway in multiple neurodegenerative diseases
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Specific GSK3 inhibitors in Phase II clinical trials in AD
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Conclusions Therapeutic target
Tau kinase induced by A b Mice and Drosophila models show reversible AD-relevant phenotypes Environmental and genetic evidence aetiologies involving dysregulation of GSK3 in AD
Potential biomarker
Altered in blood cells in AD IP retained by KHP and exploitation plans underway
Therapeutic trials underway
Lithium in AD and other neurodegenerative diseases Specific GSK3 inhibitors in AD trials Page 16
Translational pathway – GSK3 and AD
KCL
BRC Mental Health
Target identification
SLaM
Biomarker discovery Early trials/ Experimental medicine Efficacy trials
KCH, SLaM, GSTT, others
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Translational pathway – GSK3 and AD
Bench
KCL
Bedside
BRC Mental Health Dementia and mental health in later life CAG
Target identification Early trials/ Experimental medicine
BSI SLaM
Biomarker discovery
BRC-MH
Efficacy trials Page 18
• • • • •
Accelerating translation in the context of the AHSC Closer collaboration between basic and clinical sciences
– CAG structure enables and incentivises collaboration –
e.g. lithium clinics and biomarkers of GSK3 activity via BRC-MH
Closer collaboration between basic sciences
– basic science technologies ‘disease blind’ –
e.g. GSK3 signalling in development and in differentiation in the BSI
Enhanced recruitment to clinical studies
– use of IT based recruitment ; research as a mission within the NHS –
e.g. 3000 referrals to MHOA / year accessed through CRIS and BRC-MH
More effective experimental medicine
– complex interventions –
e.g. bed stays, EEG, lumbar puncture via the CRF and BRC-MH
Rapid translation of research advances
– CAG structure enables and incentivises translation –
e.g. early detection, early intervention through memory services
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Acknowledgements Current lab members and colleagues
Richard Killick Claudie Hooper Rena Meimaridou Graham Cocks Mirsada Causevic Madhav Thambisetty
Funders
– Wellcome Trust – Alzheimer’s Research Trust – Alzheimer’s Society – Medical Research Council Anna Kinsey Petra Proitsi John Powell John Stephenson Brian Anderton Page 20