Alzheimer’s: New study reveals how tau protein spreads in the brain

  • A new study investigating Alzheimer’s disease reveals that a particular type of harmful protein, known as “oligomeric tau,” may play a key role in the development of the disease.
  • High-resolution microscopy was used to discover the presence of oligomeric tau in nerve cell connections in the brains of people with Alzheimer’s, including areas previously not associated with tau buildup.
  • The findings suggest that early accumulation of oligomeric tau in nerve connections could be a precursor to Alzheimer’s, indicating that reducing these proteins may offer a promising treatment pathway.

Alzheimer’s disease (AD) is a condition that occurs when harmful proteins called tau build up and spread throughout the brain, leading to the loss of connections between nerve cells, called synapses.

While this loss in brain function has been observed in mouse models, less is known about how this occurs in humans.

While another protein called amyloid β is also found in the brains of individuals with Alzheimer’s, research suggests that the tau protein aggregates are mainly responsible for the development of the disease.

In a new study published in Neuron, researchers used a special form of high-resolution microscopy to look at tau proteins in specific regions of the brain in people with Alzheimer’s and in those who did not have the condition.

The researchers found that a specific form of tau, called “oligomeric tau,” was present in both the sending and receiving parts of the nerve cell connections, even in areas where there isn’t usually a lot of tau buildup.

Additionally, there was a higher proportion of this oligomeric tau compared to other forms of tau in these nerve cell connections.

Studying synapses with advanced microscopy

The University of Edinburgh research team focused on synapses, which are essential connections facilitating the transmission of chemical and electrical signals between brain cells.

Synapses play a crucial role in maintaining healthy brain function. In Alzheimer’s disease, large clusters of the tau protein, known as tangles, accumulate in brain cells, and this is a prominent characteristic of the disease.

As the tangles spread throughout the brain during the progression of Alzheimer’s, there is a noticeable decline in brain function.

The extent of synapse loss serves as a strong indicator of decreased memory and cognitive abilities.

During the study, researchers utilized advanced microscopy techniques to examine over one million synapses from 42 individuals, allowing the researchers to visualize the proteins within each individual synapse.

The team identified that within the synapses of individuals who had died from Alzheimer’s disease, they observed small clusters of the tau protein known as tau oligomers.

These tangles of tau oligomers were detected in both ends of the synapse, present in the brain cell that transmits signals as well as the brain cell that receives signals.

Dr. David A. Merrill, PhD, adult and geriatric psychiatrist at Providence Saint John’s Health Center in Santa Monica, CA, also not involved in the current research, told Medical News Today that the use of advanced microscopy of autopsy samples is “the first to show elevated levels of small tau oligomers in synapses of Alzheimer’s patients.”

“The tau oligomers are in addition to the misfolded and phosphorylated tau species that we know accumulate in the [Alzheimer’s] affected brain in a progressive fashion over time. The discovery that tau may spread by crossing between neurons through synaptic connections is remarkable — tau may be undergoing trans-synaptic spread.”

– Dr. David Merrill, PhD, adult and geriatric psychiatrist

Early detection of tau proteins may aid diagnosis

The new study findings suggest that the buildup of oligomeric tau in synaptic connections could be an early indicator of Alzheimer’s.

Lead researcher Prof. Tara Spires-Jones of the U.K. Dementia Research Institute at the University of Edinburgh explained the key findings in a statement, highlighting that the spread of tau throughout the brain is an important focus:

“We have known for over 30 years that tangles spread through the brain during Alzheimer’s disease, but how they spread has remained a mystery. Wherever tangles appear in the brain, neuron death follows, contributing to the decline in cognitive ability. Stopping the spread of toxic tau is a promising strategy to stop the disease in its tracks.”

– Prof. Tara Spires-Jones, lead study author

More amyloid and tau research in humans still needed

Jennifer Bramen, PhD, senior research scientist at the Pacific Neuroscience Institute in Santa Monica, CA, not involved in the study, explained to MNT that amyloid and tau are the primary molecular biomarkers in Alzheimer’s.

Still, Dr. Bramen noted that the exact role of amyloid and tau in causing the disease is still under investigation.

“This study specifically focuses on synaptic tau, a subtype that has not been extensively studied before,” Dr. Bramen said. “The paper is significant as it explores new insights into synaptic tau in humans, rather than mice.”

Dr. Bramen added that the study “focuses on soluble synaptic tau oligomers because they have been found to be more toxic to synapses and brain cells than neurofibrillary tangles (NFTs) in mouse models.”

“NFTs are more extensively studied forms of tau,” Dr. Bramen explained. “Additionally, mouse models suggest that the transmission of synaptic tau through cell-to-cell communication may be a mechanism by which synaptic loss spreads throughout the brain.”

Dr. Merrill added that “much less is known about synaptic tau and in particular synaptic oligomers in [the] human brain.”

“There is still much to learn about the neurodegenerative processes underlying [the] progression of Alzheimer’s disease and related dementias,” Dr. Merrill said.

Future treatments may target tau buildup

Dr. Merrill noted that “it may be important to develop drugs targeting these tau oligomers to protect synapses from the toxic effects of tau.”

Dr. Bramen added: “The authors of this study observed a decrease in the number of excitatory synapses in areas with this form of tau, while excitatory synapses surrounded by high amounts of NFTs did not show such a decrease.”

“Furthermore, there is evidence from this work suggesting that synaptic transmission of soluble tau leads to the spread of tau to new areas, resulting in synaptic loss in multiple regions of the human brain.

– Jennifer Bramen, PhD, neuroscientist

Dr. Bramen concluded that “these findings highlight the potential significance of targeting soluble synaptic tau in drug therapies aimed at reducing the progression of Alzheimer’s disease.”

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