Groundbreaking Study Observes Alzheimer's in Real Time with Brain Kept Alive in The Laboratory

Alzheimer’s disease is caused by the buildup of abnormal proteins in the brain that impair connections between neurons and lead to loss of memory and other functions. A new study used slices of living human brains, kept in a laboratory, to observe how these proteins behave. Scientists found that changes in the levels of these substances directly affect synapses and vary with age, brain region and even the sex of the person. This research helps to better understand the onset of the disease and may pave the way for more effective treatments.

Alzheimer’s disease is a common type of dementia that worsens over time and, unfortunately, can severely limit a person’s life. In the brain, it causes inflammation, shrinkage of brain regions (with loss of neurons and connections between them) and the buildup of two substances: beta-amyloid plaques and tangles of a protein called tau.

Science already knows that the loss of these connections, called synapses, is what most closely relates to memory and thinking problems. Therefore, understanding how these substances alter synapses in the early stages of the disease is essential to finding better treatments.

Although many studies with animal models and laboratory cells show that the accumulation of these proteins is harmful to synapses, the therapies created from this have not yet brought great results for people. Part of the problem is that these models do not accurately imitate the human brain, which is much more complex, has greater cellular diversity, lives longer and functions differently.

In recent years, medicine has made progress in tracking beta-amyloid and tau in living patients, but it is still difficult to accurately measure how these proteins behave in the healthy human brain in real time.

One method is to analyze cerebrospinal fluid (the fluid that circulates around the brain and spinal cord), where it is possible to see changes in the levels of these proteins as we age, especially in people with a genetic risk of Alzheimer's.

Other biomarkers have also been studied, such as neurogranin (which indicates damage to synapses) and KLK-6 (linked to aging), but the results are still influenced by many factors, such as the biological clock, the breakdown of the brain's protective barrier, and the way in which the body produces or eliminates these proteins.

Another more direct method of visualizing the brain is a test called PET scan, which shows the accumulation of beta-amyloid and tau over time. However, this test only detects more solid forms of these proteins, not the soluble forms (which are more toxic), and it also has limitations.

However, analyses performed after death only reveal the final stage of the disease, when the damage has already been done. There is also the collection of cerebral interstitial fluid (which directly bathes the neurons), but this procedure is very invasive and can only be performed on people who have suffered major trauma or have devices implanted in the brain.

In other words, we still know little about what actually happens in the brain of a living person throughout life, especially in relation to how synapses react to changes in beta-amyloid and tau proteins.

We know, for example, that in animals and in neurons grown in the laboratory, beta-amyloid can bind to synapses and damage them. We also know that drastic reductions in this protein can affect normal functions, indicating that it has some healthy role in the brain. The big challenge is to understand how all this happens in the real human brain, in real time.

A new technique is helping a lot: the use of slices of living human brain kept in the laboratory, obtained with permission during surgeries that would already be taking place (such as those for epilepsy or tumors). 

Human brain tissue cut into thin slices using a vibratome. Credit: University of Edinburgh

These slices are kept alive for a period of time in the laboratory and allow us to study how human neurons actually work. With them, scientists have already been able to show that the application of synthetic beta-amyloid alters the expression of genes linked to synapses and causes the absorption of this protein by brain tissue.

In the most recent study, scientists used these living slices to see how the human brain releases beta-amyloid, tau and other markers of disease. They discovered that the release of these proteins varies according to the age, region of the brain and even the sex of the person. 

Characterization of human brain slice cultures. a. The image shows an overview of how human brain slice cultures are made. It all starts with a small piece of brain tissue being removed during brain tumor surgery. This tissue is then cut into thin slices and placed in laboratory dishes to be studied. b–g. The images in b–g show these brain slices after 7 days in culture, using special dyes (immunofluorescence) to highlight different types of brain cells: MAP2: a marker of neurons, helps to visualize the "arms" of nerve cells. NeuN: another marker that shows the bodies of neurons. MAP2 (in pink) and NeuN (in yellow) combined in a single image. Iba1: shows microglial cells, responsible for "cleaning up" the brain. P2RY12: another marker of microglia, specific for when they are healthy. GFAP: shows astrocytes, the cells that support neurons. The white arrow points to a portion of an astrocyte that is wrapping itself around a blood vessel. h–i. These images show the electrical functioning of these brain slices: h. It shows how neurons respond to small electrical shocks, firing impulses, as they would normally do in the brain. i. It shows that, even at rest, neurons continue to communicate with each other with electrical signals, indicating that synapses (connections between neurons) are active. These data came from 6 patients in the cell marker test (b–g) and 5 patients in the electrical measurements (h–i).

When they artificially altered the levels of beta-amyloid, either up or down, there was a loss of connection points between neurons. However, when the levels increased a little, the brain seemed to try to compensate by activating synaptic genes.

However, when they applied beta-amyloid taken from Alzheimer's brains, the protein bound directly to the postsynaptic parts and caused loss of connections, but without activating this compensation mechanism.

These findings show that beta-amyloid has two sides: in normal amounts, it can have important functions; but when it accumulates in a pathological way, as in Alzheimer's, it becomes toxic and destroys brain connections.

The study also reinforces that these human brain slice cultures are a powerful and promising tool for better understanding what happens in the early stages of the disease and, who knows, helping to develop more effective therapies in the future.

READ MORE:

Divergent actions of physiological and pathological amyloid-β on synapses in live human brain slice cultures

Robert I. McGeachan, Soraya Meftah, Lewis W. Taylor, James H. Catterson, Danilo Negro, Calum Bonthron, Kristján Holt, Jane Tulloch, Jamie L. Rose, Francesco Gobbo, Ya Yin Chang, Jamie Elliott, Lauren McLay, Declan King, Imran Liaquat, Tara L. Spires-Jones, Sam A. Booker, Paul M. Brennan, and Claire S. Durrant

Nature Communications. 16, 3753 (2025). 30 April 2025

DOI: 10.1038/s41467-025-58879-z

Abstract:

In Alzheimer’s disease, amyloid beta (Aβ) and tau pathology are thought to drive synapse loss. However, there is limited information on how endogenous levels of tau, Aβ and other biomarkers relate to patient characteristics, or how manipulating physiological levels of Aβ impacts synapses in living adult human brain. Using live human brain slice cultures, we report that Aβ1-40 and tau release levels vary with donor age and brain region, respectively. Release of other biomarkers such as KLK-6, NCAM-1, and Neurogranin vary between brain region, while TDP-43 and NCAM-1 release is impacted by sex. Pharmacological manipulation of Aβ in either direction results in a loss of synaptophysin puncta, with increased physiological Aβ triggering potentially compensatory synaptic transcript changes. In contrast, treatment with Aβ-containing Alzheimer’s disease brain extract results in post-synaptic Aβ uptake and pre-synaptic puncta loss without affecting synaptic transcripts. These data reveal distinct effects of physiological and pathological Aβ on synapses in human brain tissue.