A study from Tel Aviv University found that the IGF-1 receptor, associated with an increased lifespan in mice, is mediating hyperactivity in the hippocampus of the brain. Hippocampal hyperactivity is linked to conditions that increase the risk for Alzheimer’s disease (AD), and the findings may pave the way for new AD treatments for early stages of the disease.
The study was published in the journal Neuron under the title “Insulin-like growth factor linked to hippocampal hyperactivity in Alzheimer’s disease.“
The hippocampus is a structure that handles memory processing, specifically spatial memory and the consolidation of short-term memory into long-term memories. An understanding of how memory storage processes work at a molecular level would also allow a deeper understanding of their failures, such as in AD and other forms of late-life dementia.
The research team, led by Dr. Inna Slutsky, used cultured brain tissue and slices to study the information processes in the hippocampus on all levels, ranging from protein interactions over synapses and neuronal connections to the entire hippocampal network. Signaling in the hippocampus can be divided into a spontaneous mode of transmission and evoked by active nerve signaling, and the two signaling modes are often controlled by different factors. The team specifically wanted to know if IGF-1 receptors are involved in spontaneous synaptic signaling, and how they affect synaptic function in the hippocampus.
The researchers studied single synapses in living cells using a technique called fluorescence resonance energy transfer (FRET), and found that the IGF-1 receptor was actively modulating the release of neurotransmitters from the synapse during spontaneous nerve signaling.
The team then tried to enhance the activity of the receptors by treating the cells with IGF-1. That approach did not elicit any effect, but blocking the receptor led to an increased release of neurotransmitters during basal conditions. On the other hand, neurotransmitter release following active nerve signaling was blocked. The IGF-1 receptor was, in other words, controlling both spontaneous and evoked signaling in the hippocampus.
“When we modified the level of IGF-1R expression, synaptic transmission and plasticity were altered at hippocampal synapses, and an increase in the IGF-1R expression caused an augmented release of glutamate, enhancing the activity of hippocampal neurons,” Neta Gazit, who performed the experiments, said in a press release.
Slutsky added, “People who are at risk for AD show hyperactivity of the hippocampus, and our results suggest that IGF-1R activity may be an important contributor to this abnormality. We suggest that IGF-1R small inhibitors, which are currently under development for cancer, be tested for the reduction of aberrant brain activity at early stages of Alzheimer’s disease.”
The researchers are now planning to examine how IGF-1R contributes to the stability of neural circuits over a longer period of time.