A window into memory loss in Alzheimer’s disease

Alzheimers is a particularly cruel disease. It erodes people’s memories – loved ones are in many ways ‘lost’ long before they ever die.

But we’re gradually learning more about how Alzheimer’s develops and why — and treatments are improving. An unanswered question is whether the memory problems in Alzheimer’s disease are related to the recording of memories, or whether it becomes more difficult to ‘replay’ memories.

Researchers are trying to understand the mechanisms behind how Alzheimer’s disease affects memory. Photo: Getty Images

This is important because if Alzheimer’s disease is primarily a signaling problem, it suggests that there may be ways to devise therapies that could ‘save’ these patients’ memory by ‘sharpening’ the signal.

In a collaboration between medicine and electrical engineering, we used a ‘camera in the brain’ technique to find evidence that when mimicking the effects of Alzheimer’s disease in mouse models, memory traces were still present, but became much less apparent – such as a blurry video screen.

U.S Resultspublished in the magazine Frontiers in neurosciencesuggest that memories in Alzheimer’s disease may remain intact, but the signal for replaying these memories is impaired by interference — or what we call noise.

The effects of Alzheimer’s disease can be mimicked in animals with a drug called scopolamine temporarily affecting memory.

Our challenge was to figure out how to directly monitor the activity of neurons in the brain to find clues to exactly what’s going on, while putting the mice through a simple memory test — navigating a linear track.

This is where the ‘camera in the brain’ comes into play.

It involved a graduate electronics research student, Dechuan Sun, who implanted a lightweight and removable miniaturized fluorescence microscope — called a miniscope — on top of a mouse’s head. This allowed us to observe brain cells in action in the mouse hippocampus, an area that codes for new memories and is highly affected by Alzheimer’s disease.

A graphical representation of how a miniscope works. Graphics: Included

Fluorescent microscopes work by detecting signals from Green fluorescent protein (GFP) linked to a calcium sensor molecule (known as GCaMP) added to cells to “lighten” various cellular operations.

The discovery and development of GFP won the Nobel Prize in Chemistry in 2008 and involves introducing a gene derived from a bioluminescent jellyfish into a cell.

To generate detectable light signals when neurons are activated, GCaMP DNA is introduced into the cells using a benign viral carrier, Adeno-associated virus (AAV). The neurons then generate their own GCaMP that changes fluorescence when neurons are discharged.

The fluorescence changes because when a neuron is activated, calcium flux binds to the protein and changes the intensity of the fluorescence. This activity can then be detected by shining light with the appropriate spectral properties onto the neurons.

This light comes from the miniscope.

The technology and engineering for using small head-mounted miniscopes to monitor the brain was developed by: Professor Mark Schnitzer at Stanford University.

Our miniscope weighs about three grams and has a small plastic lens about 1.8 millimeters in diameter that sits in a small hole in the skull. The lens is directly above the brain tissue, which means that the brain tissue is not affected.

The images are then recorded directly onto a camera sensor chip similar to those in our cell phones, and the data is then transported to a computer using a single one millimeter thick coaxial wire.

Mouse neurons marked with Green Fluorescent Protein. Image: Professor M. Hausser, University College London/Wellcome Trust

The thinness and lightness of the wire is important to minimize any inconvenience to the animal, but using such a thin wire requires clever computer coding to compress the data.

The great advantage of the fluorescent miniscope is that it allows researchers to monitor activity in large areas of the brain, allowing us to see how hundreds of neurons interact in an extensive network – there is no other practical way to do this. to do.

And the fluorescent compounds can last for months, allowing us to monitor the brain behavior of animals over longer periods of time.

In our experiments, the mice could still “remember” how to find the food reward on the linear track, but the miniscope showed us that the memory signals the mice received were impaired.

More research is needed to better understand what’s going on, but this work could potentially illuminate a path to finding restorative therapies using memory drugs.

It could also point the way to being able to “resynchronize” brain signaling to reduce the noise caused by Alzheimer’s disease, possibly through techniques like deep brain stimulation.

According to the World Health OrganizationMore than 55 million people live with dementia worldwide, with Alzheimer’s disease accounting for up to 70 percent of those cases. And this number increases as the population ages.

By 2030, the number of cases is expected to reach 78 million and by 2050 there will be 139 million.

And this tells us that the need to better understand Alzheimer’s disease is only going to become more urgent.

Banner: Getty Images

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