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Previously unknown tau pathway leading to Alzheimer’s disease identified.

It is known that during disease, tau protein gets modified, changes its location in nerve cells and then aggregates.  In healthy nerve cells, tau resides in a part of the nerve cell termed the axon, the long, slender part of the cell that carries electrical impulses away from the neuron’s body.  Dendritic mislocalization of microtubule-associated tau protein is a hallmark of tauopathies, however, the role of dendritic tau is unknown.  Now, a study from researchers at Boston University School of Medicine (BUSM) shows a previously unknown pathway leading to neurodegeneration in Alzheimer’s disease (AD) which may unlock the door to new approaches for treating the disease.  The team state that their findings also raise the possibility that the tauopathies, such as Alzheimer’s disease, are associated with dysfunction of RNA-binding proteins (RBPs) biology.  The opensource study is published in the journal Cell Reports.

Previous studies show that RBPs are a class of about 800 proteins that function in the nucleus to regulate mRNA maturation.  RBPs also function in the cytoplasm where they regulate RNA translation, trafficking, sequestration, and degradation.  Increasing evidence links neurological disease processes to dysfunction of neuronal RBPs, RNA granules, and stress granules (SGs).  SGs are a particular type of RNA granule that accumulates during the translational response to stress.  Earlier studies from the lab and others show that RBP mutations increase RNA granule formation, leading to SGs that are larger and more abundant.  Formation of pathological RNA granules is associated with neuropathology with RBPs, such as T cell intracellular antigen 1 (TIA1) shown to co-localize with neuropathology in brain tissue of subjects with Alzheimer’s disease.  The current study shows that tau promotes SG formation and modulates the patterns of protein interactions of TIA1, a main SG component.

The current study shows that the tau protein directs the formation of stress granules, which are molecular complexes that allow nerve cells to adapt to stresses, such as injury. Results show that the tau-stress granule complex is usually short-lived, however, in the setting of chronic stress, tau persistently forms into a cluster, leading to the degeneration of nerve cells seen in Alzheimer’s disease.

The group explain that the nerve cells do this to stimulate formation of stress granules, which help the cell to adapt under stressful conditions. They go on to add that stress granules instruct the cell to divert energy toward making protective proteins and away from making specialized proteins, which are less necessary during stress.

Results show that the association of tau with stress granules also caused tau to cluster, with most stresses short-term and quickly resolved.  The researchers state that some stresses are chronic, such as vascular disease or the accumulation of beta-amyloid, a protein that accumulates outside the neuron in Alzheimer’s disease.  They observed that chronic stress leads to excessive, persistent accumulation of stress granules containing aggregated tau, which ultimately damages nerve cells, leadiung to degeneration.

The team surmise that they found that reducing the amount of one of the key stress granule proteins, TIA1, prevented tau aggregation and nerve cell degeneration and that while still in its early stages, their work points to entirely new approaches to treating Alzheimer’s disease.  For the future, the researchers state they are now planning to test their research findings in animal models of Alzheimer’s disease.

Source: Boston University School of Medicine (BUSM)


Researchers identify new pathway leading to Alzheimer's disease - neuroinnovations

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