Novel drug developed to treat type 2 diabetes are neuroprotective Alzheimer s disease
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1 Novel drug developed to treat type 2 diabetes are neuroprotective Alzheimer s disease Prof. Christian Hölscher, PhD Biomed and Life Sciences Faculty of Health and Medicine Lancaster University, UK
2 Alzheimer s disease About 4.5 million people in Europe have AD 28 million people worldwide Will double by 2040 due to ageing population
3 Diabetes- a risk factor in AD Insulin not only acts as a hormone to regulate blood glucose Insulin acts as a growth factor in all tissues Protects neurons of oxidative stress effects Inhibits apoptosis, promotes cell repair Enhances neuronal proliferation and dendritic sprouting in neurons Insulin signaling in the AD brain de-sensitises
4 Diabetes a risk factor for Alzheimer s disease Neurology, 2011, 77: Type 2 Diabetes sufferers have a % increased risk of developing AD
5 Insulin signaling is desensitised in AD patients Insulin signaling is reduced in non-diabetic AD patients brains Brain analysis shows a reduction of Insulin Receptor signaling The biochemical profile in the brain is similar to those in diabetic people in the periphery
6 Novel strategies for treatments Testing diabetes drugs that prevent the desensitisation of insulin signaling Accessing parallel signaling pathways- the incretin hormones (GLP-1, GIP) Making use of the findings from diabetes research Prevention of neurodegeneration at an early stage
7 Currently on the market to treat type 2 diabetes: Twice daily: Exendin-4 (Byetta ; Exenatide ) Once daily: Liraglutide (Victoza ), Lixisenatide (Lyxumia ) Once-weekly: Albiglutide (Tanzeum ; Eperzan ), Dulaglutide (Trulicity ) Once-weekly version of Byetta (Bydureon ) Others are under development
8 Chronic studies of Lixisenatide or Liraglutide in a mouse model of AD Transgenic mouse strain expressing human mutated APP and PSN1 genes that cause Alzheimer s Develops plaques in the brain, memory loss, synapse loss, chronic inflammation
9 Memory is rescued by the drugs Object recognition task Recognition index (RI) APP/PS1 SALINE Recognition index (RI) APP/PS1LIXI 10nmol/kg A B Novel * Novel ns p= Familiar p= Familiar Recognition index (RI) APP/PS1 LIRA 25nmol/kg C * Novel p= Familiar A = saline B = 1nm Lixisenatide C = 10nm Lixisenatide D = 2.5nm Liraglutide E = 25nm Liraglutide Recognition index (RI) APP/PS1 LIXI 1 nmol/kg D * Novel p= Familiar Recognition index (RI) APP/PS1 LIRA 2.5 nmol/kg E Novel ns p= Familiar McClean et al., 2014
10 McClean et al., 2014 Synapse numbers increased Density of synapses histology APP/PS1 Saline APP/PS1 Lixisenatide (1nmol/kg) APP/PS1 Liraglutide (2.5nmol/kg) APP/PS1 Lixisenatide (10nmol/kg) APP/PS1 Liraglutide (25nmol/kg) Wild-type Saline Polymorph layer of hippocampus Granular cell layer Molecular layer OD D D D D ** D D D ** D D D OD D D * OD D D D D D ** A B C 0.0 Stratum radiatum Stratum pyramidal Stratum oriens OD D D 0.4 ** D D D D D D 0.2 D 0.0 E 0.0 F OD 0.4 * 0.2 OD D D D D D **
11 Amyloid plaques are reduced Beta-amyloid plaque load in the cortex Beta amyloid plaque load (% stained area) APP/PS1 Saline APP/PS1 Lixisenatide (1nmol/kg) APP/PS1 Liraglutide (2.5nmol/kg) APP/PS1 Lixisenatide (10nmol/kg) APP/PS1 Liraglutide (25nmol/kg) -49% -46% -43% -45% ** McClean et al., 2014
12 Chronic inflammation is reduced Level of activated microglia in the brain is reduced Activated (IBA-1) microglial load (% stained area) % -48% -43% * * ** APP/PS1 Saline APP/PS1 lixisenatide (1nmol/kg) APP/PS1 liraglutide (2.5nmol/kg) APP/PS1 lixisenatide (10nmol/kg) APP/PS1 liraglutide (25nmol/kg) Wild-type Saline -49% ** -82% McClean et al., 2014
13 Testing liraglutide in AD patients in a pilot clinical trial Study design: 38 patients, placebo controlled study, 6 months duration, PET imaging of 18 FDG, amyloid. Results: - Liraglutide prevented the decline of brain activity as shown in 18 FDG-PET brain imaging
14 18 FDG-PET imaging: Neuronal metabolism is compromised in AD AD patient control subject In 18 FDG-PET imaging: - Progressive decline of glucose uptake over time - Correlates well with cognition and disease progression Femminella and Edison, 2014
15 18 FDG-PET study: Liraglutide prevents reduction in metabolism Abstract ADA 2015 Gejl et al., 1309-P
16 Abstract ADA 2015 Gejl et al., 1309-P
17 Our clinical trial, testing liraglutide in AD patients Liraglutide- phase II clinical trial (UK) 200 MCI/AD patients, placebo controlled double blind study, 12 months duration, PET imaging of FDG uptake and also of inflammation markers, CSF and blood analysis of tau / amyloid biomarkers, ADAS-cog cognitive test battery, daily living score Funded in part by:
18 Thanks to: Neuroscience group Prof. Christian Hölscher Dr. Paula McClean Dr. Kerry Hunter Dr. Simon Gengler Dr. Mohit Sharma Emilie Faivre Vadivel Parthsarathy Jaishree Jalewa Aisling Duffy Dora Panagaki UU Diabetes group Prof. Peter Flatt, Dr. Victor Gault Prof. Konrad Talbot Neurology dept., Cedars-Sinai hospital, L.A., USA Prof Guanglai Li Dr. Guo Fang Xue Neurological hospital, Taiyuan, China Prof. Lin Li Prof. Jinshun Qi Shanxi Medical University Taiyuan, China
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