Alzheimer's Tau protein forms toxic complexes with cell membranes

November 22, 2017, Ecole Polytechnique Federale de Lausanne
PET scan of a human brain with Alzheimer's disease. Credit: public domain

The brains of patients with Alzheimer's disease contain characteristic tangles inside neurons. These tangles are formed when a protein called Tau aggregates into twisted fibrils. As a result, the 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.

Given its role in the pathology of Alzheimer's disease, Tau has been extensively investigated. With several clinical trials of amyloid-targeting therapies failing recently, Tau has become one of the most actively pursued therapeutic targets for Alzheimer's disease. However, questions still remain about how Tau spreads in the brain and kills neurons. The cell membrane has been shown to play a role in regulating Tau's aggregation properties and physiological functions, but we still do not understand how the interplay between Tau and lipid membranes can lead to the loss of neurons seen in Alzheimer's disease.

Now, the lab of Hilal Lashuel at EPFL, in collaboration with the lab of Thomas Walz at the Rockefeller University, found that individual Tau proteins interact with and disrupt the cell membrane of neurons. This disruption gives rise to highly stable complexes made up of several Tau proteins as well as fat molecules (phospholipids) from the membrane.

Subsequent studies showed that the protein/phospholipid 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. The hippocampus is where memory is processed, and loss of is a classic symptom of Alzheimer's disease. The complexes were detectable with an antibody (MC-1) that 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," says Nadine Ait Bouziad, the PhD student who led the study.

In collaboration with Professor David Eliezer at Weill Cornell School of Medical Sciences in New York, the researchers 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 are called PHF6* and PHF6, and they 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 -dependent mechanism that regulates Tau structure, oligomerization, toxicity, and possibly its normal and aberrant trafficking between and within ," says Hilal 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."

Explore further: Chemical engineers help decipher mystery of neurofibrillary tangle formation in Alzheimer's brains

More information: Nadine Ait-Bouziad et al, Discovery and characterization of stable and toxic Tau/phospholipid oligomeric complexes, Nature Communications (2017). DOI: 10.1038/s41467-017-01575-4

Related Stories

Chemical engineers help decipher mystery of neurofibrillary tangle formation in Alzheimer's brains

November 2, 2011
Neurofibrillary tangles – odd, twisted clumps of protein found within nerve cells – are a pathological hallmark of Alzheimer's disease. The tangles, which were first identified in the early 1900s by German psychiatrist ...

Peptide complex in the brain is responsible for Alzheimer's disease

July 17, 2017
Members of the Faculty of Fundamental Medicine at the Lomonosov Moscow State University have determined the structure of a peptide complex formed in the brain at the early stages of Alzheimer's disease. The research results ...

Researchers focus on cell membranes to develop Alzheimer's treatments

March 23, 2017
Thin parts of the cell membranes of neurons turn out to be particularly vulnerable to a protein that collects in the brain of people with Alzheimer's disease, according to a University of Michigan researcher.

Researchers unlock the molecular origins of Alzheimer's disease

September 6, 2017
A "twist of fate" that is minuscule even on the molecular level may cause the development of Alzheimer's disease, VCU researchers have found.

Researchers reveal unusual chemistry of protein with role in neurodegenerative disorders

July 27, 2017
A common feature of neurodegenerative diseases is the formation of permanent tangles of insoluble proteins in cells. The beta-amyloid plaques found in people with Alzheimer's disease and the inclusion bodies in motor neurons ...

ALS protein dynamics highlight delicate balance between self-association and aggregation

January 6, 2016
The ALS-related protein TDP-43 takes the first steps toward pathologic aggregation as part of its normal function, according to a new study publishing in the Open Access journal PLOS Biology on Jan. 6, 2016. The study, by ...

Recommended for you

A new way of thinking about tau kinetics, an essential component of Alzheimer's disease

March 21, 2018
Alzheimer's disease is most often characterized by two different pathologies in the brain: plaque deposits of a protein called beta-amyloid and tangles of another protein called tau. A paper appearing March 21 in the journal ...

Could drugs used after an organ transplant protect against Alzheimer's?

March 21, 2018
A UT Southwestern study in mice provides new clues about how a class of anti-rejection drugs used after organ transplants may also slow the progression of early-stage Alzheimer's disease.

Cell therapy could improve brain function for Alzheimer's disease

March 15, 2018
Like a great orchestra, your brain relies on the perfect coordination of many elements to function properly. And if one of those elements is out of sync, it affects the entire ensemble. In Alzheimer's disease, for instance, ...

Physically fit women nearly 90 percent less likely to develop dementia

March 14, 2018
Women with high physical fitness at middle age were nearly 90 percent less likely to develop dementia decades later, compared to women who were moderately fit, according to a study published the March 14, 2018, online issue ...

Poor sleep may heighten Alzheimer's risk

March 12, 2018
(HealthDay)—Older adults who are sleepy during the day might have harmful plaque building in their brain that is a sign of impending Alzheimer's disease, researchers report.

Dementia patients with distorted memories may actually retain key information – researchers say

March 7, 2018
Some memories containing inaccurate information can be beneficial to dementia sufferers because it enables them to retain key information researchers say.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.