The Tenets of Tauists Knowing Neurons

For the labs working tirelessly to understand the underpinnings of Alzheimer’s disease, there are often two camps: BAPtists and tau-ists.  The former subscribe to the beta amyloid cascade hypothesis that implicates amyloid plaque deposition as the primary culprit in causing memory loss and degeneration.  In this model, neuronal cell loss and axonal transport problems associated with the disorder occur as a consequence of plaque formation.  The beta amyloid theory has dominated the discussion; however, compelling insight is shifting the discussion to tau-induced neurotoxicity.

The Tenets of Tauists Knowing Neurons
In a PETPositron emission tomography (PET) involves injecting a mole... More scan, the protein tau is illuminated in the hippocampusStructure in temporal lobe that has many functions but is es... More of a person suspected to have Alzheimer’s diseaseA neurodegenerative disease characterized by neuronal loss i... More.

Alzheimer's Cell Amyloid TauAlzheimer’s disease is a tauopathy because the microtubule-associated protein tau accumulates in the brains of individuals with the disease forming hyperphosphorylated tau tangles that trigger abnormal DNA oxidation.  In exciting research published in Nature Neuroscience, researchers recently uncovered how tau can lead to a loss of heterochromatin and an increase in abnormal geneA sequence of nucleic acids that forms a unit of genetic inh... More expression that contributes to neurodegeneration.  Chromatin at its most basic level is the complex of DNA and proteins that make up the nucleus.  Chromatin is necessary to prevent DNA damage, control gene expression, and package DNA. Stability of gene expression is dependent on a normal balance of chromatin.  In the nucleus, there are specific chromatin domains: euchromatin, which is permissive for gene activation, and heterochromatin, which is repressive.

The researchers (most likely tauists) used Drosophila or fruit flies as a model organism to examine the link between changes in chromatin and tau neurotoxicity.  They expressed a mutant form of human tau in the neurons of fruit flies and observed progressive degeneration.  There are two heterochromatin proteins, H3K9me2 and HP1a, that are highly conserved (similar in nucleotide and protein sequence) in both flies and humans.  The total levels of these two proteins decreased in the brains of flies expressing tau compared to the controls suggesting that loss of heterochromatin might occur in Alzheimer’s disease.  The severity of degeneration correlated with how severe the loss of chromatin was.

Alzheimer's_disease-neuron_deathWe discussed earlier that heterochromatic DNA is highly condensed and tightly packaged, making it less accessible to transcription factors for gene activation.  The researchers wanted to understand if the loss of heterochromatin protein directly caused cell death in their fly model of tau-mediated degeneration.  To test this, the team restored heterochromatin formation by genetically manipulating genes that would promote its formation.  In the aftermath of restoring the heterochromatin, they found that the amount of cell death was decreased in the fly model of tau-induced Alzheimer’s disease.  Furthermore, when the researchers reduced the H3K9me2 and HP1a heterochromatin proteins to extremely low levels (even lower than that caused by tau expression alone) they found that they doubled the level of cell death!  This result indicates that loss of normal heterochromatin promotes neurodegeneration and gives evidence for faith in the tauist model of degeneration.

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References:

Frost B., Hemberg M., Lewis J. & Feany M.B. (2014). Tau promotes neurodegeneration through global chromatin relaxation, Nature Neuroscience, 17 (3) 357-366. DOI:

Top image adapted from Maruyama M., Shimada H., Suhara T., Shinotoh H., Ji B., Maeda J., Zhang M.R., Trojanowski J., Lee V.Y. & Ono M. & (2013). Imaging of Tau Pathology in a Tauopathy Mouse Model and in Alzheimer Patients Compared to Normal Controls, NeuronThe functional unit of the nervous system, a nerve cell that... More, 79 (6) 1094-1108. DOI:

Other images from the National Institute on Aging and Wikimedia Commons.

Jillian L. Shaw

Jillian decided to dedicate herself to a life of exploring the mysteries of the brain after reading neurological case studies by Oliver Sachs and Ramachandran as a student at Vassar College.After completing a B.A. in Neuroscience with honors in 2009, Jillian headed to USC to pursue a Ph.D. in Neuroscience where she is now in her 5th year.A research stint in Belgium exposed Jillian to the complexities of cell signaling pathways, and her interests shifted from cognitive neuroscience to cellular and molecular neuroscience.Her current research focuses on the link between Down syndrome and Alzheimer’s disease using Drosophila as a genetic model to explore axonal transport, mitochondria dysfunction, synaptic defects, and neurodegeneration.When she is not in the lab, Jillian is forming new synapses by rock climbing throughout Southern California.

Jillian L. Shaw

View posts by Jillian L. Shaw
Jillian decided to dedicate herself to a life of exploring the mysteries of the brain after reading neurological case studies by Oliver Sachs and Ramachandran as a student at Vassar College. After completing a B.A. in Neuroscience with honors in 2009, Jillian headed to USC to pursue a Ph.D. in Neuroscience where she is now in her 5th year. A research stint in Belgium exposed Jillian to the complexities of cell signaling pathways, and her interests shifted from cognitive neuroscience to cellular and molecular neuroscience. Her current research focuses on the link between Down syndrome and Alzheimer’s disease using Drosophila as a genetic model to explore axonal transport, mitochondria dysfunction, synaptic defects, and neurodegeneration. When she is not in the lab, Jillian is forming new synapses by rock climbing throughout Southern California.

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