Therapeutic Strategies for Cognitive Dysfunction in People with Down Syndrome
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1 Therapeutic Strategies for Cognitive Dysfunction in People with Down Syndrome Ahmad Salehi, M.D., Ph.D VA Palo Alto Health Care System & Department of Psychiatry & Behavioral Sciences, Stanford Medical School
2 Down Syndrome: A Malady of Angels Adoration of the Christ Child, 1515 AD, Source: Met Museum of Arts
3 Characteristics of Down Syndrome Physical Features: - Dysmorphic facial features - Growth retardation
4 Characteristics of Down Syndrome Central Nervous System: - Intellectual disability (I.Q ) - Cognitive dysfunction - Attention deficit & hyperactivity (ADHD)
5 Characteristics of Down Syndrome Cardiovascular System: Cardiac malformations - Septal defects - Tetralogy of Fallot - Patent ductus arteriosus Leading cause of mortality in Down syndrome
6 Characteristics of Down Syndrome Musculoskeletal System: - Dysplasia of the pelvis - Hypotonia
7 Characteristics of Down Syndrome Gastrointestinal System: - Intestinal atresia - Abnormalities of anus - Hirschprung s disease (absence of nerve cells in bowelwall)
8 Alzheimer s Disease Pathology in Adults with Down Syndrome
9 Process of Drug Development Define the problems Discover genes and mechanisms Deliver treatment Discover treatments
10 Mouse Models of Down Syndrome
11 Target Abnormal Circuits Overexpression of specific genes on HSA21 Abnormal Circuits Cognitive Dysfunction
12 Dentate Gyrus Undergoes Significant Atrophy in Ts65Dn Mice
13 Quantification of Dendritic Tree in DGCs ML DGC PML Dentate Gyrus
14 A Significant Loss of Dendritic Arborization in DGCs in Ts65Dn Mice
15 Hippocampal Function is Modulated by Subcortical Regions with Extensive Projections
16 Locus Coeruleus Neurons Send Extensive Projections to the Rest of the Brain Particularly the Hippocampus
17 Locus Coeruleus Neurons Undergo Significant Degeneration in Ts65Dn Mice IV IV 2N- 6m 2N Ts65Dn- 6m
18 Strategies to Increase Norepinephrine (NA) Levels in Ts65Dn Mice 1) Increasing brain NE levels. 2) adrenergic agonists.
19 Method of Increasing Norepinephrine Levels in the Brain
20 Failure in Contextual Learning in Ts65Dn Mice
21 Frontal Cortex Hippocampus Loss of Locus Coeruleus Neurons in Mouse Models of AD APP V717I APP V717I +Dsp4 AB AB 42 P< APP/PS1 APP/PS1 + Dsp4 Heneka et al., Proc Natl Acad Sci U S A. 2010
22 L-DOPS is able to restore cognitive function in the Ts65Dn mouse model of Down syndrome nut it is yet to be approved by the FDA
23 Targeting β1 or β2 Adrenergic Receptors? 1) Cardiovascular complications are the most common cause of death in DS. 2) b2 gene expression is more than beta1 in DGCs 3) Effects of NE on LTP is mediated by 2. 4) b2 mediates the effects of NE on ADE. 5) b2 polymorphism has been linked to dementia of AD. 6) b2 mediates the positive effects of NE on neurogenesis.
24 β2 Adrenergic Receptors in Dentate Granule Cells ML DGC
25 Formoterol (FORM) is a long-acting specific β2- adrenergic receptor agonist used for the treatment of asthma.
26 No Adverse Effects of Formoterol on Respiratory System
27 Formoterol Reduces Open Field Activity in Ts65Dn Mice Velocity Total Distance Travelled
28 Formoterol Improves Spatial Learning in Ts65Dn Mice
29 Short Term Use of formoterol Leads to a Significant Increase in the Synaptic Density in the Dentate Gyrus in Ts65Dn Mice
30 Increased Density of C-Fos-positive Neurons in the Dentate Gyrus of Ts65Dn mice
31 Doublecortin Labels Newly-born Cells Destined to Become Neurons
32 Formoterol Significantly Increases the Dendritic Complexity of New-born Neurons
33 Formoterol Significantly Increases the Dendritic Complexity of New-born Neurons III II I
34 Acknowledgments: Van Dang, DVM, Ph.D Kara Martin, MS Sarah Moghadam, Pharm. D. Brian Medina, BS Priyanka Naik, BS Devan Patel, MD Bill Lin, BS Devsmita Das, MD, MPH Martha Millan Sanchez, MD Sri Patchala, MD Vincent Wong, BS Wes Ashford, M.D, Ph.D UCSD Bill Mobley Pavel Belichenko
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