MAR 19, 2014 7:00 AM PDT

Therapeutic Strategies for Cognitive Dysfunction in Down Syndrome

Presented at: Neuroscience
Speaker
  • Clinical Associate Professor Department of Psychiatry & Behavioral Sciences, Stanford Medical School
    Biography
      Ahmad Salehi, M.D., Ph.D. is a Clinical Associate Professor at the Department of Psychiatry and Behavioral Sciences, Stanford Medical School and the Director of the Translational Laboratory at the VA Palo Alto Health Care System in California. He obtained his MD in Tehran, Iran and then moved to the Netherlands Institute for Brain Research, in Amsterdam to get his PhD. While he was there, he was selected as the best junior scientist in the field of Alzheimers disease in the Netherlands. After finishing his graduate studies and 3 years of postdoc in Amsterdam, he moved to Stanford Medical School. First as a postdoc, and then as a Senior Research Associate, he worked on mechanisms of failed axonal transport in mouse models of Down syndrome. For almost a decade, he was the Director of Stanford Brain Bank. Since 2009, Dr. Salehi has moved to the Department of Psychiatry and Behavioral Sciences at Stanford. In December 2010, he received the World Technology Award in the field of Biotechnology for his innovative work on the use of mouse models of Down syndrome. During his carrier, Ahmad has been involved in publication of a large number of papers from which several have appeared on the cover of Science, Cell: Stem Cell, Science Translational Medicine, Neuroscience and Bio-behavior Reviews, and Biological Psychiatry (twice).

    Abstract

    Down syndrome (DS) is a complex multi-system disorder affecting more than 5.8 million individuals around the world and it causes significant physical, psychological, and cognitive abnormalities in affected individuals. Later in adulthood, all individuals with DS develop brain pathology indistinguishable from that of Alzheimer's disease (AD). To understand the neurobiological basis of cognitive dysfunction in DS, we have used the Ts65Dn mouse model of DS. Similar to both DS and AD, these mice show significant age-dependent degeneration of cholinergic neurons in the basal forebrain and norepinephrine (NE)-ergic neurons in the locus coeruleus. Among around 300 genes triplicated in DS, the triplication of amyloid precursor protein (APP) plays a significant role in the pathophysiology of cognitive dysfunction in DS. Interestingly, we found that App over-expression is both sufficient and necessary for degeneration of both cholinergic and NE-ergic systems. We have focused on restoring NE-ergic system as a therapeutic strategy for cognitive dysfunction in DS. The critical role of NE-ergic system in cognitive dysfunction in Ts65Dn has been supported by the fact that increasing brain NE levels with L-DOPS, i.e. a NE prodrug, restored contextual learning in Ts65Dn mice. L-DOPS was just approved by the FDA for use in the treatment of hypotension. To identify an alternative agent to improve NE signaling in DS and to expedite the process of drug development, we aimed to test the effects of adrenergic drugs on cognitive function that have already been approved for use in humans. In the periphery, a majority of β1ARs are found in the cardiovascular system. Formoterol is a long-acting adrenergic receptor agonist. We found that the use of formoterol in adult Ts65Dn mice was safe and led to a significant improvement in contextual learning and restoration of synaptic density in the dentate gyrus in Ts65Dn mice. Furthermore, formoterol treatment was linked to a significant increase in the rate of cell proliferation and dendritic complexity of newly born neurons in the dentate gyrus of the hippocampus in Ts65Dn mice. Our investigation revealed that improving β2 adrenergic signaling led to a significant increase in the density of microglia in the dentate gyrus of Ts65Dn mice. Since microglia activation has been linked to increased Aβ clearance, our data suggests that improving adrenergic signaling might also reduce the severity of Aβ pathology in adults DS showing significant AD-related pathology. All these data support the idea that improving NE-signaling particularity activation of β2 adrenergic receptors might be an effective strategy in improving cognitive function in both AD and DS.


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