Mecanismo de acción de Souvenaid: nuevos datos preclínicos
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1 Mecanismo de acción de Souvenaid: nuevos datos preclínicos Dra. Sagrario Manzano Coordinadora del Grupo de Neurología de la Conducta y Demencias de la SEN. Hospital Universitario Infanta Cristina. Parla. Madrid
2 # synapses dentate gyrus (x10 10 ) Synapse loss is structural basis of deficits in people with AD; our lead for intervention target Reduced number of synapses 10 * % -44% Control MCI AD Synapse loss AD is confirmed in >30 publications
3 Meta-analysis of synapse loss and synaptic pathology in AD Meta-analysis highlights the presence of synapse loss and synaptic pathology in AD Synapse numbers are lower in AD A variety of synaptic protein markers are lower in AD Changes in hippocampal pre-and postsynaptic markers Meta-analysis of synapse numbers in the hippocampus de Wilde, et al. (2016) Alz&Dement
4 Insight behind our approach: Dietary precursor control of neural membrane synthesis The Kennedy pathway for biosynthesis of neuronal membrane Synapses consist principally of neuronal membranes dendritic Axon spine terminal neurite Dendritic spine Neurite Axon Kennedy & Weiss (1956) J. Bio. Chem. 222, Prof Richard Wurtman at MIT, Boston, USA
5 Insight behind our approach: Dietary precursor control of neural membrane synthesis The Kennedy pathway for biosynthesis of neuronal membrane Synapses consist principally of neuronal membranes Kennedy & Weiss (1956) J. Bio. Chem. 222, Prof Richard Wurtman at MIT, Boston, USA
6 Dietary precursors can be rate-limiting: synergy between dietary precursors Brain phospholipids (PE) *** * Control (choline) UMP DHA UMP + DHA Wurtman, et al. Brain Res. 2006
7 Van Wijk, et al. Nutr Metab B-vitamins enhance the bioavailability of DHA and choline via the PEMT pathway Dietary B-vitamin enrichment leads to elevated plasma choline levels Dietary B-vitamin enrichment leads to elevated plasma DHA levels
8 Dietary phospholipids increase precursor availability Phospholipids as cofactor Dietary phospholipids enhance the absorption of DHA and EPA from the gut into the enterocytes and the lymph increased availability of DHA and EPA Van Wijk, et al., Lipids means without a common letter differ, p < 0.05
9 Choline (μmol/l) Dietary phospholipids increase precursor availability PL Phospholipids as a precursor Dietary phospholipids are digested into several phospholipid precursors: Fatty acids Lysophospholipids, phosphatidic acid Glycerol, monoglycerides Choline and ethanolamine Dietary phospholipids increase rat plasma and brain choline Increased plasma choline Control Fish oil Fish oil + PLs Van Wijk, et al., Lipids. 2016
10 Insight behind our approach: Dietary precursor control of neural membrane synthesis The Kennedy pathway for biosynthesis of neuronal membrane Synapses consist principally of neuronal membranes dendritic Axon spine terminal neurite Dendritic spine Neurite Axon Kennedy & Weiss (1956) J. Bio. Chem. 222, Prof Richard Wurtman at MIT, Boston, USA
11 Insight behind our approach: Dietary precursor control of neural membrane synthesis The Kennedy pathway for biosynthesis of neuronal membrane Synapses consist principally of neuronal membranes Kennedy & Weiss (1956) J. Bio. Chem. 222, Prof Richard Wurtman at MIT, Boston, USA
12 Fortasyn increases membrane phospholipid levels in the hippocampus of aged rat Results confirm effects of DHA+UMP on synaptic membrane formation Time-dependent effects Cansev, et al. Neurobiol Aging, 2015
13 Fortasyn nutrients increase neurite outgrowth Neurite outgrowth in PC12 cells after 2 day supplementation with NGF + different nutrients Savelkoul et al. (2016) Alz&Demen
14 Wiesmann, Zerbi, et al. Neural Plast, 2016 Cansev, et al. Neurobiol Aging, 2015 Fortasyn increases pre- and postsynaptic protein levels in the hippocampus of aged rats Presynaptic Postsynaptic in hippocampal and cortex areas of aged mice (wild-type and AD risk model, ApoE4) Postsynaptic
15 Fortasyn nutrients improve membrane receptor function and density Muscarinic G protein-coupled receptor activation in vitro PC12 cells APP/PS1 mice Savelkoul, et al. J Neurochem Janickova, et al. Curr Alzheimer Res Complete Fortasyn mix induces the largest effect
16 Fortasyn increases cholinergic transmission in the hippocampus of aged rats Microdialysis in freely moving rats CA1 region of hippocampus Fortasyn diet vs. Control diet 4 or 6 weeks dietary intervention Acetylcholine tissue levels Acetylcholine release Acetylcholine tissue levels also increased by FC ChAT levels ChAT levels increased by FC ChAT is the enzyme that synthesizes acetylcholine from choline and acetyl- CoA FC increases acetylcholine release Basal and after stimulation with atropine Time-dependent effects Cansev, et al. Neurobiol Aging, 2015
17 VAChT positive cells NBM ChAT positive cells NBM Fortasyn protects against abeta toxicity in a rat model of AD Protection of cholinergic cells Choline acetyl-transferase (Chat) 400 * ICV Abeta1-42 infusion Resembling AD pathology 200 Abeta Sham Abeta Sham Abeta Control Fortasyn Connect* Vesicular acetylcholine transporter (VAChT) 300 * Sham Abeta Sham Abeta Control Fortasyn Connect* de Wilde, et al. JAD 2011
18 Beta-amyloid production Fortasyn reduces AD pathology Transgenic mouse model of Alzheimer pathology 4 mo 7 mo 10 mo Broersen et al., 2013 JAD
19 Fortasyn preserves integrity of white and gray matter in the brain of APP/PS1 mice diffusion-tensor MRI White matter loss (reduced FA) is observed in APP/PS1 mice on Control diet but not on Fortasyn diet; a diet with only fish oil and UMP (DEU) is less effective Gray matter loss (increased MD) is observed in APP/PS1 mice on Control diet but not on Fortasyn or DEU diet Fortasyn is most effective Zerbi, et al. Neurobiol Aging. 2014
20 Fortasyn improves cerebral blood flow and cerebral blood volume Reduced cerebral blood flow in APP/PS1 mice is restored by fish oil and UMP (DEU) diet and Fortasyn diet Zerbi, et al. Neurobiol Aging Wildtype APPswe/PS1dE9 Now replicated in ApoE-4 mice and normal mice (Wiesmann, Zerbi, et al. Neural Plast 2016) In ApoE-ko mice, a vascular risk model for dementia, Fortasyn increased relative cerebral blood volume in midbrain and cortical areas Jansen, Zerbi, et al. Brain Struct Funct. 2014
21 Escape latency (s) Fortasyn improves cognition in APP/PS1 mice Water maze learning Control Fish oil Fortasyn Spatial learning in the water maze is improved in APP/PS1 mice on a Fortasyn diet Fish oil diet has no effect Fortasyn is most effective * * Control Fish oil Fortasyn Days Koivisto, et al. J Nutr Biochem. 2014
22 Precursors & cofactors enhance synapse formation & function Summary basic science Key phenomena being studied 1.Cansev (2005) Brain Res 2.Ulus (2006) Cell Mol Neurobiol 3.Van Wijk (2011) Br J Nutr 4.Van Wijk (2012) Nutr Metab 5.Wurtman (2006) Brain Res 6.Wang (2005) J Mol Neurosci 7.Pooler (2005) Neuroscience Increase precursor supply Co-factors increase precursor availability Increase phosphatide / membrane synthesis Improved membrane composition Increase neurite outgrowth Increase connectivity (grey and white matter integrity) Increase synaptic proteins Increase synaptic contacts Increase neurotransmission (ACh synthesis, release, receptors) Synergy between nutrients Reduced abeta production/plaque formation/toxicity Reduced neurodegeneration (immunoreactivty & NAA) Improve learning & memory / behavior 8.Sakamoto (2007) Brain Res 9.Farkas (2002) Brain Res 10.Wang (2007) Brain Res 11.Kariv-Inbal (2012) JAD 12.Grimm (2011) JBC 13.Teather (2003) PNBP 14.de Wilde (2003) Brain Res 15.de Wilde (2002) Brain Res 16.de Bruin (2003) J Learn Mem 17.Holguin (2008) BehavBrainRes 18.van Wijk (2014) JAD 19.de Wilde (2011) J Alz Dis 20.Cansev (2012) data on file 21.Cansev (2015) Neurobiol Aging Confirmed & Published Nutrient combinations Fortasyn Connect 1,2,34 3,4, 34 2,5,8,11,17,34,35 11,23 6,7 2,5,7,8,35 8 2,6,9,10 5,7,8,17,34,35 11,12 22.Jansen (2013) PLOS ONE 23.Broersen (2013) J Alz Dis 24.Savelkoul (2012) AAIC 25.Zerbi (2014) Neurobiol Aging 26.Savelkoul (2011) ADPD 27.Savelkoul (2016) in prep 28.Savelkoul (2012) J Neurochem 11, ,22, ,32 21, ,21,28,33 24,26,28 19,23 19,22,23,29 19,22, Jansen (2013) Brain Struc Fun 30.Koivisto (2014) J Nutr Biochem 31.Wiesmann (2013) JAD 32.Wiesmann (2016) Neur Plas 33.Janickova (2015) Curr Alz Res 34.van Wijk (2016) Lipids 35.Van Wijk (2016) AAIC
23 Putative effects of Fortasyn nutrients on membrane-related pathology in AD Van Wijk, et al. JAD 2014
24
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