Stanford researchers in the Department of Neurology have discovered a method for improving cognitive functions in mouse models of Down syndrome (DS) and Alzheimer's Disease by increasing norepinephrine (NE) levels in the hippocampus. In particular, droxidopa (also known as L-threo-3,4-dihydroxyphenylserine or L-DOPS) is a potential therapeutic agent for these conditions. This approach is based on extensive research indicating that locus coeruleus in the brainstem and the main supplier of hippocampal NE, undergoes severe degeneration in mouse models of DS and Alzheimer's disease. By using either droxidopa (a prodrug that easily passes through the blood brain barrier and is converted to NE) or NE receptor agonists, xamoterol, it was possible to reverse the cognitive failure in Ts65Dn mouse model of DS. To limit the effects of droxidopa to the CNS, the inventors used carbidopa, which inhibits the conversion of droxidopa to NE but does not cross the blood brain barrier.Stage of Research
In two sets of independent studies, the inventors found that droxidopa treatment can efficiently reverse cognitive failure in a mouse model of DS. In the study, the inventors showed that:
• Young adult Ts65Dn mouse models of DS show significant age dependent degeneration of locus coeruleus.
• As the result, there is a significant reduction in the levels of NE in the hippocampus of aged Ts65Dn mice.
• Degeneration of locus coeruleus in Ts65Dn mice is linked to failure in two hippocampally-mediated cognitive behaviors, i.e. contextual learning and nesting.
• Using droxidopa and/or xamoterol (see above), the inventors were able to reverse both failure in contextual learning and also decreased nesting in Ts65Dn mice.
• The degeneration of locus coeruleus is also linked to amyloid precursor protein (App) gene overexpression. A gene whose mutations always lead to familial forms of Alzheimer's disease.
• The inventors also proposed specific ways to start with clinical trials in young adults as well as children with DS. This includes the use of droxidopa in young adults with DS and NE reuptake inhibitors in children with DS.
• Recent data published by independent groups has shown that increasing brain NE levels, would significantly improve cognitive function and reduce amyloid pathology in the brain of mouse models of Alzheimer’s disease.