Today’s research materials report on recently presented preliminary evidence, based on work in tissue slices from mouse brains, for oxytocin to dampen the harms done to the function of neurons by amyloid-β. Amyloid-β is one of the few proteins in the body capable of becoming altered in ways that encourage other molecules of amyloid-β to alter in the same way, aggregating into solid deposits in and around cells. This is disruptive to cell function when it occurs in the brain, and rising amyloid-β aggregation is widely thought to be the early, formative stage of Alzheimer’s disease.
Oxytocin is one of the factors that diminishes with age in blood, identified as potentially interesting in parabiosis studies of recent years. This work was largely focused on the role of oxytocin in muscle regeneration via its influence on stem cell function, however. More recently, increasing oxytocin and lowering TGF-β in combination was shown to reverse measures of aging in numerous tissues in mice. That, again, seems to be a matter of effects on inflammation and stem cell function rather than something more specific such as an influence on cell mechanisms relevant to amyloid-β.
Alzheimer’s disease is a progressive disorder in which the nerve cells (neurons) in a person’s brain and the connections among them degenerate slowly, causing severe memory loss, intellectual deficiencies, and deterioration in motor skills and communication. One of the main causes of Alzheimer’s is the accumulation of a protein called amyloid β (Aβ) in clusters around neurons in the brain, which hampers their activity and triggers their degeneration.
Studies in animal models have found that increasing the aggregation of Aβ in the hippocampus – the brain’s main learning and memory center – causes a decline in the signal transmission potential of the neurons therein. This degeneration affects a specific trait of the neurons, called synaptic plasticity, which is the ability of synapses (the site of signal exchange between neurons) to adapt to an increase or decrease in signaling activity over time. Synaptic plasticity is crucial to the development of learning and cognitive functions in the hippocampus. Thus, Aβ and its role in causing cognitive memory and deficits have been the focus of most research aimed at finding treatments for Alzheimer’s.
Researchers first perfused slices of the mouse hippocampus with Aβ to confirm that Aβ causes the signaling abilities of neurons in the slices to decline, impairing synaptic plasticity. Upon additional perfusion with oxytocin, however, the signaling abilities increased, suggesting that oxytocin can reverse the impairment of synaptic plasticity that Aβ causes. In a normal brain, oxytocin acts by binding with special structures in the membranes of brain cells, called oxytocin receptors. Expectedly, when the receptors were blocked, oxytocin could not reverse the effect of Aβ, which shows that these receptors are essential for oxytocin to act.
Oxytocin is known to facilitate certain cellular chemical activities that are important in strengthening neuronal signaling potential and formation of memories, such as influx of calcium ions. Previous studies have suspected that Aβ suppresses some of these chemical activities. When the scientists artificially blocked these chemical activities, they found that addition of oxytocin addition to the hippocampal slices did not reverse the damage to synaptic plasticity caused by Aβ. Additionally, they found that oxytocin itself does not have any effect on synaptic plasticity in the hippocampus, but it is somehow able to reverse the ill-effects of Aβ.
Oxytocin, a peptide hormone synthesized in the hypothalamic paraventricular nucleus, has been reported to participate in the regulation of learning and memory performance. However, no report has demonstrated the effect of oxytocin on the amyloid-beta (Aβ)-induced impairment of synaptic plasticity. In this study, we examined the effects of oxytocin on the Aβ-induced impairment of synaptic plasticity in mice.
To investigate the effect of oxytocin on synaptic plasticity, we prepared acute hippocampal slices for extracellular recording and assessed long-term potentiation (LTP) with perfusion of the Aβ active fragment (Aβ25-35) in the absence and presence of oxytocin. We found that oxytocin reversed the impairment of LTP induced by Aβ25-35 perfusion in the mouse hippocampus. These effects were blocked by pretreatment with the selective oxytocin receptor antagonist L-368,899. Furthermore, the treatment with the ERK inhibitor U0126 and selective Ca2+-permeable AMPA receptor antagonist NASPM completely antagonized the effects of oxytocin.