A Critical Immune Protein Helps the Brain Link Memories, and Could Combat Aging
May 31, 2022
Memories are like scenes in a movie, and the brain is an excellent video editor.
Take a normal day as an example. A morning routine—shower, coffee, checking emails—is seamlessly cut into one continuous scene. Other goings-on throughout the day become separate cuts, so when recalling one memory—a fabulous bagel sandwich deli, for example—the memory pops into the mind on its own. Yet ultimately we still retain a continuous narrative of our lives that shapes who we are, without memories blending into each other in an incomprehensible plot.
How does the brain do that?
A new study in Nature points to a surprising clue—a protein called CCR5. The name may sound familiar. It’s well known as an entryway for HIV infection. It’s also the gene that skyrocketed to fame in 2018, when a rogue scientist used CRISPR-Cas9 to engineer the world’s first gene-edited babies, triggering a global backlash and landing him in prison.
Part of the worry for the babies is that CCR5 is a multitasker. In the brain, for example, it dwells in cells at high levels in the hippocampus, a region critical for memory. CCR5 has previously been linked to memory functions, prompting questions on how the edits could alter the babies’ cognition down the line.
The new study offers additional clues. In mice, CCR5 acts as the scissor tool in video editing. As the brain continuously processes new experiences into memories, high levels of CCR5 essentially snip the timeline into distinct episodes. While normally helpful, CCR5 levels rise during aging and often become overzealous. The result is memory loss—a mind that struggles to link memories into comprehensive events.
“Our memories are a huge part of who we are,” said study lead author Dr. Alcino Silva at the David Geffen School of Medicine at UCLA. “The ability to link related experiences teaches us how to stay safe and operate successfully in the world.”
The good news? Using an FDA-approved drug for HIV treatment, the team restored an aging mind’s ability to link memories in mice, “a result that could have substantial clinical implications,” the team said.
Let’s Talk Memory
Memories may seem like amorphous wisps inside a mind, but they have strong neurobiological underpinnings.
When we encounter new experiences, a select group of neurons inside a part of the hippocampus encodes these data. How these neurons are selected is still relatively mysterious, but scientists have engineered ways to “prime” certain neurons to participate in the memory so that they’re more active and likely to participate.
Once a memory is stored, this network of neurons is called an engram. The process is very loosely similar to a computer allocating memory storage to save a new document. Activating any component of the engram triggers the whole network to activate, which retrieves the memory.
This process relies on a dance of a myriad of proteins. Neurons are like hotels with multiple protein locks—receptors—and keys, called ligands. The locks are generally dotted on the surface of the cell. Each requires the right key to unlock it. Unlocking triggers a cascade of molecule signaling inside cells, which eventually changes how a neuron behaves; it might get more excitable, or more inhibited and less inclined to network with others. Less networking means less memory encoding, and potentially less memory linking.
“How does the brain know that two events are occurring closely in time? Addressing this question requires an understanding of how time is encoded in memory—a major unknown in memory research,” said Andrea Teceros and Dr. Priya Rajasethupathy at the Rockefeller University, who were not involved in the study.
In the new study, the team honed in on CCR5 as a key protein to delink a memory stream. Although mostly known as part of the immune system, CCR5 is a receptor highly expressed in the hippocampus, and previous studies suggested a potential role in memory.
The team began with a popular setup for memory tests for mice. They first placed the mice into one cage to explore, and five hours later, placed them into a different cage with wildly different decorations. Here the mice received a quick and mild electrical zap, enough to startle them and make them freeze in fear. This encoded two different memories. Two days later, when placed back into the first benign cage, the mice also froze—showing that they’ve linked the first cage and the second, where they actually received the shock, into one memory.
The time gap was key. When the team extended the five-hour gap between the two cages to 24 hours, the mice could no longer link the memories.
The switch turned out to be CCR5. The protein levels briefly shot up 12 hours after the initial encoding, and tanked soon after—a trajectory that parallels the time course for memory linking. Genetically deleting or inhibiting CCR5 prolonged the memory linking window so that the mice could still hook up memories of the two cages up to seven days apart. In contrast, increasing CCR5 further dampened the mice’s ability to link those memories.
Digging deeper, CCR5 seems to directly tinker with neural activity in the hippocampus—the memory ledger—to dampen its activity. Two memories close in time often share overlapping engrams. Here, mice without CCR5 had greater overlaps between memories of the two cages and higher memory linking compared to normal counterparts.
Aging Memory Treatment?
Like most immune molecules, CCR5 levels rise with age, suggesting they may increasingly hack apart memories. This led the team to wonder: can we inhibit the protein to boost memory function with age?
They tested the theory in middle-aged mice with an FDA-approved drug for HIV, maraviroc, that inhibits the protein’s functions. A single infusion directly into the “memory center” hippocampus improved the aging animal’s ability to link memories, spread five hours apart, in a subsequent test. Similarly, middle-aged mice genetically lacking CCR5 also linked up memories better than their normal peers.
“When we gave maraviroc to older mice, the drug duplicated the effect of genetically deleting CCR5 from their DNA…the older animals were able to link memories again,” said Silva.
To Terceros and Rajasthupathy, the results could help with memory loss. “Because memory deficits in aging and in Alzheimer’s disease might be dominated by deficits in retrieval (and thus memory linking) rather than memory storage, which involves separate brain circuits, these results could have clinical implications.”
The study is one of the first to interrogate the brain’s clock for memory linking and segregation. It opens up a world of new questions. How does memory linking affect learning? Can it help “time-stamp” memories during storage in the mind? As an immune molecule, how does CCR5 further influence memory and other cognitive functions? And what, if anything, happens when human embryos are shoddily deprived of the molecule, as in the case of the CRISPR babies?
For now, the team is mostly eyeing CCR5’s therapeutic potential. “Our next step will be to organize a clinical trial to test maraviroc’s influence on early memory loss with the goal of early intervention,” said Silva. “Once we fully understand how memory declines, we’ll possess the potential to slow down the process.”
Image Credit: geralt / 24463 images
Shelly Xuelai Fan is a neuroscientist-turned-science writer. She completed her PhD in neuroscience at the University of British Columbia, where she developed novel treatments for neurodegeneration. While studying biological brains, she became fascinated with AI and all things biotech. Following graduation, she moved to UCSF to study blood-based factors that rejuvenate aged brains. She is the …
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