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.
Medical Laboratory Technician50%
Manufacturer - Other33%