Shy neurons in a model of Alzheimer's disease

What exactly is wrong with Grandma’s brain when she can’t remember the day of the week, or maybe even the year? Sensory information is processed in the brain by sending electrochemical signals along a specific cell type called a neuron. If neurons fail to transmit a signal properly, neurodegeneration can result.

The underlying causes of Alzheimer’s disease are still being discovered in an intense laboratory race against the clock. Like all organs, the brain is composed of an assortment of cells that are shaped and controlled by instructions stored in DNA. One contributing factor to familial Alzheimer’s, a form of the disease that can be passed down through family members, is a gene mutation. Genes are segments of DNA that code for a single piece of the cellular machinery. The set of genes in question are called the presenilin genes, of which humans have two normal versions called presenilin-1 and presenilin-2.

Chen Zhang from the Harvard Medical School recently connected another piece of the puzzle by identifying a potential role of presenilin genes in Alzheimer’s pathogenesis. Mutations in the presenilin genes have been thought to cause neurodegeneration by disrupting the function of the synapse (the site where one neuron communicates with another). Zhang’s team sought to determine if mutated presenilin genes created a problem in the synapse by affecting neurons sending a signal or by affecting those receiving a signal. Using transgenic mice, Zhang disrupted presenilin genes in both types of neurons.

Following stimulation of the mutated neurons with a pulse of electricity, the strength of neuron-to-neuron communication was measured. Zhang’s team found that disruption of presenilin in the neuron sending a signal decreased the strength of signal transmission, while no effect was observed when presenilin activity was eliminated in neurons receiving signals.

In stimulated neurons, calcium plays an important role in the neuron’s ability to release chemicals into the synapse. Upon further investigation, Zhang and colleagues found an upset in calcium balance within the neurons upon presenilin elimination. Subsequently, the signal-sending neurons were no longer able to release the proper amount of chemicals to communicate with their down-stream partners.

Prior to this study, a large portion of research had been focused on cellular events in the signal-receiving neurons. It is now clear that disruption in the neurons that send signals may play an equally important role in the propagation of Alzheimer’s disease pathogenesis. Indeed, other neurodegenerative diseases, such as Parkinson’s disease, are also associated with gene mutations that affect the signal-sending neuron. Perhaps a flaw in the signal-sending events during neural information processing is a more general contribution to the pathogenesis of neurodegeneration than previously thought.

The Bottom Line: A mutation in mouse presenilin genes affects a neuron’s capacity to send signals, stemming from an inability to control chemical release during neuron-to-neuron communication.

Reference:
Zhang et al. “Presenilins are essential for regulating neurotransmitter release.” Nature Vol 460, 30 July 2009, doi: 10.1038/nature08177.