Alzheimer’s: Study zeroes in on brain’s weakest link

In Alzheimer’s disease, as in other forms of dementia, a defining feature is the accumulation of certain toxic proteins in the brain.

These proteins aggregate into plaques that disrupt the communication between brain cells, thus enhancing cognitive problems and other issues.

More often than not, researchers identify the protein beta-amyloid as the main culprit in this disruptive process.

However, another protein, called tau, is just as important.

In a new study, researchers from a series of academic institutions, including the Ohio State University in Columbus, Columbia University Medical Center in New York, NY, and Cambridge University in the United Kingdom, have found that tau accumulates preferentially around a specific type of brain cell.

The investigators also revealed that certain genetic profiles may predispose a person to tau aggregations around those cells.

Co-lead author of the study Hongjun (Harry) Fu — now an assistant professor in the Department of Neuroscience at Ohio State University — and colleagues report their findings in a paper recently published in Nature Neuroscience.

The most vulnerable brain cells

The brain contains different types of cells. The two most important are neurons, which communicate information and play a key role in cognitive function, and glial cells, which have several roles, including supporting and protecting neurons and the connections between them.

Neurons fall into two types: excitatory, which trigger electrical impulses, and inhibitory, which balance out the activity of excitatory neurons.

Studying the phenomenon of tau protein accumulation in a mouse model, as well as in the brains of people who have received Alzheimer’s diagnoses, Fu and colleagues found that excitatory neurons were those most exposed to the disruptive effect of this protein.

“The accumulation of misfolded tau aggregates is a defining feature of Alzheimer’s disease and frontotemporal lobar degeneration linked to tau,” the researchers write, adding, “Several types of neurons have been reported to be particularly vulnerable in [Alzheimer’s disease], Down’s syndrome, and [frontotemporal lobar degeneration].”

“The distribution of neurons vulnerable to tauopathy follows a sequential pattern that suggests that cell populations in different regions of the brain are selectively at risk. More specifically, the morphology and location of cells within the entorhinal cortex and hippocampus that accumulate tau […] suggest that excitatory neurons are preferentially impacted.”

Following this finding, the researchers compiled genetic analyses based on the data of people who did not have either Alzheimer’s disease or any other neurological issues.

The investigators noticed some important genetic differences between the excitatory and inhibitory neurons, which, they believe, could explain why the former are more exposed to tau aggregation.

Could genes explain the phenomenon?

Specifically, the researchers found that one gene, BAG3, which regulates the clearance of tau protein in the brain, may provide the key to excitatory neurons’ susceptibility to toxic plaque formation.

BAG3 expression, the team explains, was much higher in neuronal cells than in non-neuronal cells. Among neurons, the expression was highest in the inhibitory type, suggesting that this could explain their reduced vulnerability to tau aggregates.

“We think there’s a really early, intrinsic difference in the brain cells that are prone to the accumulation of tau protein, which may explain why only certain neurons and brain regions are vulnerable to this problem in early Alzheimer’s,” says Fu.

“If we can figure out the molecular determinants underlying vulnerability to this disease, it will help us better understand the development of Alzheimer’s disease and potentially could lead to techniques for early detection and targeted treatment,” he adds.

In the future, the researchers aim to focus on how interactions between certain genes could influence Alzheimer’s-specific mechanisms and enhance brain cells’ vulnerability to toxic plaques.

The investigators note that brain cells other than neurons also likely play an important role in the progression of neurodegenerative conditions, including Alzheimer’s.

“Other brain cells, including microglia, astrocytes, and oligodendrocytes, have also been found to play important roles in the development of Alzheimer’s disease,” Fu notes, adding, “We are very interested to understand how those cells communicate with each other and affect the vulnerability of certain neurons.”

The researcher explains, “Environmental factors, brain injury, diabetes, sleep deprivation, depression, and other outside factors also have been linked to increased vulnerability to Alzheimer’s,” continuing, “We want to understand how intrinsic differences interact with these outside influences.”

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