Alzheimer's plaques play bigger role

Alzheimer's plaques play bigger role

Researchers in the US studying mice with and without amyloid-beta plaques in their brains (the plaques that are characteristic of Alzheimer's disease) found that contrary to current thinking, the plaques don't just damage the neurons they are close to but may well affect signalling in other parts of the brain through their influence on extensive networks of astrocyte brain cells.

The study was the work of researchers from the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) at Massachusetts General Hospital in Charlestown, and is published in the 27 February online issue of Science.

Simply speaking, mammals have two main types of brain cell: neurons that send electrical and chemical signals and glia cells that support, control, and look after them. An astrocyte is a type of star-shaped glia cell that not only provides passive support to neurons, but as scientists discovered in the 1990s, they also send signals using calcium ions that move from cell to cell like waves, and these waves can travel a long way in the brain.

Astrocytes are found everywhere in the brain and they account for about half the volume of it.

Plaques are left over bits of cell that clump together and stick to neurons, disrupting their ability to send signals; they are more common in older brains and one of the hallmarks of Alzheimer's disease.

The authors explained in their background information that although we already know that senile plaques disrupt the neurons they stick to (focal disruption), we don't know much about how astrocytes behave in Alzheimer's disease. With this study they showed that senile plaques make astrocytes hyperactive; not just the ones nearby, but also others quite far away from the focal neuron site.

Lead author Kishore Kuchibhotla of MGH-MIND told the press:

"Our work suggests that amyloid plaques might have a more complex role in altering brain function than we had thought."

"Plaques develop rapidly and have been shown to cause relatively acute, localized neuro-toxicity," he added, explaining that their work shows astrocytes "could provide a network mechanism that may stretch the impact of plaques to more distant areas of the brain."

For this study Kuchibhotla and colleagues used a method called "multiphoton fluorescence lifetime imaging microscopy" to measure and trace the calcium waves travelling along astrocyte networks in the brains of gentically altered laboratory mice with and without some of the hallmarks of Alzheimer's disease, such as the amyloid-beta plaques. (Using a dye they "labelled" astrocytes so that when they were active they lit up and when they switched off they went dark).

They found that resting calcium levels were high throughout the astrocyte network in mice with plaques, not just where they happened to be near individual plaques.

Using time-lapsed images they found that changes in calcium waves in astrocytes were more frequent and synchronized across long distances and uncoupled from what was happening near the neurons.

The researchers also found some rare calcium waves travelling between cells: these were only present in mice with amyloid-beta plaques and the waves appeared to start near plaques and spread radially from them for at least 200 micrometers.

They concluded that:

"Although neurotoxicity is observed near amyloid-[beta] deposits, there exists a more general astrocyte-based network response to focal pathology."

Kuchibhotla said that:

"This is the first clear evidence in a live animal model that amyloid plaques perturb calcium signaling across the astrocyte network via a neuron-independent mechanism."

"It has been suggested that these intercellular calcium waves, which previously had been observed only in response to some sort of external stimulus, indicate the existence of or response to a traumatic insult," he added, explaining that while their results support this idea, what we still don't know is whether the calcium signals they observed actually protect or harm cells.

"We've only begun to scratch the surface of how plaque deposition impacts astrocyte function," said Kuchibhotla.

An important question for future research will be how the increased activity of astrocytes affects the ways neurons work, and another will be whether it increases or limits the formation of plaques.

"Synchronous Hyperactivity and Intercellular Calcium Waves in Astrocytes in Alzheimer Mice."

Kishore V. Kuchibhotla, Carli R. Lattarulo, Bradley T. Hyman, and Brian J. Bacskai.

Science 2009, 323, 1211 published online 27 February 2009.

DOI: 10.1126/science.1169096

Click here for Abstract.

Sources: Journal abstract, Massachusetts General Hospital press statement.

Alzheimer's disease - plaques, tangles, causes, symptoms & pathology (Video Medical And Professional 2020).

Section Issues On Medicine: Medical practice