Reboxetine Treatment Reduces Hippocampal Gliosis in the P301S Tauopathy Mouse Model

The loss of brain noradrenergic neurons is one of the earliest alterations observed in Alzheimer's disease and other neurodegenerative pathologies. The consequent reduction of brain noradrenaline levels facilitates the progression of neuroinflammatory processes that can be fatal for neurons and other brain cells. For this reason, compensating for noradrenaline deficit through different means constitutes an interesting therapeutic strategy. Drugs that inhibit the reuptake of noradrenaline are used to elevate the extracellular concentrations of this neurotransmitter and potentiate this way its effects. These drugs are approved for the treatment of depression or attention deficit hyperactivity disorder, among other indications, but their repurposing and use in Alzheimer's disease could be of interest given the beneficial effects observed for noradrenaline in numerous studies. Based on this, we previously showed the beneficial effects of reboxetine, a noradrenaline reuptake inhibitor, on 5xFAD mice that accumulate amyloid beta in their brains and reproduce some of the typical alterations of Alzheimer's disease. In this study we have analyzed the effects of reboxetine on P301S mice, a different model of Alzheimer's disease based on the expression of mutant forms of human microtubule-associated protein tau. We observed that the administration of reboxetine with osmotic pumps for 28 days to 9-month-old mice reduced the accumulation and activation of microglia and astrocytes in different areas of the hippocampus. These findings indicate that reboxetine treatment prevents the neuroinflammatory response known to cause brain damage in Alzheimer's disease even when the treatment is initiated at an advanced stage of the disease.