Targeting specific astrocyte brain-cell receptors found to boost memory in mice

A drug that targets those receptors could improve memory in Alzheimer's disease
January 27, 2015

Astrocytes are stained in red, the A2A receptors in green, the overlap between the two shows as yellow, and the cell nuclei are in blue (credit: Anna Orr/Gladstone Institutes)

Gladstone Institutes researchers have uncovered a new memory regulator in the brain that may offer a potential treatment to improve memory in Alzheimer’s disease using a drug that targets those receptors.

They found in their research* that decreasing the number of A2A adenosine receptors in astrocyte brain cells improved memory in healthy mice. It also prevented memory impairments in a mouse model of Alzheimer’s disease.

The findings were published Monday (Jan. 26) in Nature Neuroscience.

Astrocytes’ important role in memory

Astrocytes have been traditionally seen as mere support cells for neurons — providing nutrients, for example — but recently, neuroscientists have recently found evidence that astrocytes demonstrate surprising effects on object-recognition memory and cognitive behavior and help the brain respond to visual stimuli and play a role in remembering visual stimuli, as KurzweilAI has reported.

“Our findings have provided us not only with a new perspective on the role of astrocytes in cognition, but also with an exciting drug target to enhance memory and maybe even stave off memory decline in Alzheimer’s disease,” says senior author Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease and professor of neurology and neuroscience at the University of California, San Francisco.

Repurposing drugs … and caffeine; human trials considered

Astrocyte (Wikimedia Commons)

“Next, we will explore the therapeutic implications of our discovery by re-purposing available drugs for their memory enhancing potential,” especially ones that block these adenosine receptors and are well tolerated in humans.

Their study also provides support for other research suggesting that caffeine (whose main target is, you guessed it, adenosine receptors) may improve normal memory function or even prevent Alzheimer’s symptoms in older adults.

These efforts could culminate in a trial in humans.

But the scientists say that they were surprised that the effect of manipulating astrocytes was restricted to long-term memory, with no changes occurring in learning or general behaviors. “Given the many roles of astrocytes in the brain, one might expect a global disruption of brain function,” says lead author Anna Orr, PhD, a staff scientist at Gladstone. “Instead, we see a very specific effect on memory retention.”

* To solve this mystery, the researchers focused on astrocytes after their initial finding that patients with Alzheimer’s disease have unusually high numbers of adenosine receptors in these cells. However, whether this increase was linked to cognitive ability was unknown.

So the scientists generated mice with normal or reduced levels of A2A receptors in astrocytes and compared them on tests of learning and memory. While the mice showed no differences in learning, those that had fewer adenosine receptors performed better on tests of long-term memory. Moreover, reducing the number of receptors improved memory in older mice that often have memory deficits.

Taking this one step further, the researchers performed the same experiments in a mouse model of Alzheimer’s disease to see if these astrocytic adenosine receptors were also involved in memory loss associated with the disease. Once again, decreasing the number of receptors improved memory, even in the presence of amyloid plaques characteristic of Alzheimer’s.

The researchers confirmed their findings by repeating some of the experiments using chemical manipulations of astrocyte receptor activity instead of relying on permanent genetic changes. Importantly, this suggests that it may be possible to improve memory and treat Alzheimer’s disease using a drug that targets these receptors.


Abstract of Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory

Astrocytes express a variety of G protein–coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer’s disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.