Tau protein, one of the main culprits implicated in Alzheimer’s disease, and the cell membrane are as thick as thieves. Tau and the membrane are, in fact, suspected of putting molecular events into motion that favor tau’s aggregation within neurons. These events are poorly understood, but their effects are not. When tau aggregates, neurons' transport systems disintegrate, essential nutrients can't move through, and the cells begin to die, affecting the brain's functions and giving rise to the disease's symptoms.

To better understand how the interplay between tau and lipid membranes can lead to the loss of neurons seen in Alzheimer's disease, scientists based at Ecole Polytechnique Fédérale de Lausanne (EPFL) and Rockefeller University have studied how individual tau proteins interact with and disrupt the cell membrane of neurons. The scientists have found that tau’s disruption of the cell membrane gives rise to highly stable complexes. These complexes, the scientists report, consist of several tau proteins as well as fat molecules (phospholipids) from the membrane.

Details appeared of this work appeared November 22 in the journal Nature Communications, in an article entitled  “Discovery and Characterization of Stable and Toxic Tau/Phospholipid Oligomeric Complexes.” The article shows that these complexes are more readily taken up by neurons compared to the fibril form of the protein, and induce toxicity in primary neurons of the hippocampus in vitro.

“These complexes…are detected by MC-1, an antibody recognizing pathological Tau conformations,” wrote the article’s authors. “The core of these complexes is comprised of the PHF6* [paired helical filament 6*] and PHF6 hexapeptide motifs, the latter in a β-strand conformation.”

The hippocampus is where memory is processed, and loss of hippocampal neurons is a classic symptom of Alzheimer's disease. The complexes were detectable with MC-1, which is used as a standard for detecting pathological conformations of tau, meaning that they share some features of the pathological form of the protein.

“Our goal was to identify the sequence and structural factors that drive tau interaction with membranes and the formation of these complexes so that we can develop strategies to interfere with their formation and block their toxicity,” said Nadine Ait Bouziad, the study’s lead author and a Ph.D. student in the EPFL laboratory of Hilal Lashuel, Ph.D. Lashuel worked in collaboration with Rockefeller’s Thomas Walz, Ph.D., and Weill Cornell’s David Eliezer, Ph.D.

The team used nuclear magnetic resonance (NMR) to gain insight into the structure of tau in the core of the complexes. This revealed that the cores are made up of two small peptides, each only six amino acids long. These peptides, PHF6* and PHF6, play important roles in driving tau aggregation and assembly into fibrils. Their presence connects the protein/phospholipid complexes with the development of Alzheimer's disease.

Building on their findings, the researchers were able to produce mutant tau protein. The introduced mutations disrupted tau's ability to interact with cell membranes, but did so without interfering with its ability to form fibrils. The idea behind this is that such mutants can be used to uncouple these two processes, which would allow researchers to investigate the effect that these membrane interactions have on the function, aggregation, and toxicity of tau in primary neuron cultures. This would be a first step in gaining a clearer picture of how tau tangles begin to form, which would be critical if we are to develop efficient therapies to counteract their toxicity.

“Our findings point toward a novel form of tau protein/phospholipid complexes that might be part of a membrane-dependent mechanism that regulates tau structure, oligomerization, toxicity, and possibly its normal and aberrant trafficking between and within neurons,” stated Lashuel. “By developing tools that allow us to detect, disrupt, and/or target these complexes, we hope to identify novel strategies to inhibit tau aggregation, toxicity, and pathology spreading in the Alzheimer's brain.”

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