US researchers have discovered that a drug currently used for treating Alzheimer's can either improve or worsen the progression of Huntington's disease (HD) depending on where the brain cells it targets are located.
Published this week in Nature Medicine, the findings may offer a new therapeutic approach towards Huntington’s disease.
HD is a condition characterised by the death of neurons (brain cells) in the brain region called the striatum, which plays an important role in planning and executing movement. The disease is caused by mutations in the gene encoding the protein huntingtin, and results in the formation of huntingtin aggregates in the affected neurons; these aggregates may have a protective role early in the disease.
The researchers used mice with mutant forms of huntingtin. They studied the link between HD, the excessive excitatory brain activity observed, and the huntingtin aggregate formation. The team tested the effect of different doses of the drug memantine. This drug inhibits NMDA receptors in the brain, which are a key subtype of the main excitatory receptors in the brain.
They found that a low dose of memantine blocked NMDA receptors found outside of the synapse (where one neuron passes a signal to another) and therefore reduced the severity of HD in the mice — such as neuronal death and behavioural deficits. By contrast, a high dose of memantine that blocked NMDA receptors found on both the synapse and outside of the synapse decreased the number of huntingtin clumps and in fact worsened the disease.
The study also revealed that the location of NMDA receptors on the neuron determines whether their activation will lead to aggregate formation and neuronal survival or to aggregate dissolution and neuronal death. Importantly, memantine is already used in the clinic to treat patients with Alzheimer’s disease, therefore tinkering with its dose to only target NMDA receptors in certain cellular locations may help with Huntington’s treatment.
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