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Neuronal Death And Processing Of Tau Protein In Alzheimer's Disease

Date:
April 1, 2005
Source:
International School For Advanced Studies In Trieste
Summary:
In a new study, researchers show that a processed form of tau protein induces neuronal death by apoptosis (programmed cell death) when expressed in cultured rat hippocampal neurons. Pathological changes in the microtubule associated protein tau are a major hallmark of the human dementias collectively defined as tauopathies, including Alzheimer's disease.

In a research report recently published in the Journal of Alzheimer's Disease (http://www.j-alz.com), published by IOS Press, a research group from the International School for Advanced Studies (ISASSISSA) in Trieste (Luisa Fasulo, Gabriele Ugolini e Antonino Cattaneo) showed that a processed form of tau protein induces neuronal death by apoptosis (programmed cell death) when expressed in cultured rat hippocampal neurons. Pathological changes in the microtubule associated protein tau are a major hallmark of the human dementias collectively defined as tauopathies, including Alzheimer's disease (AD). In Fronto-Temporal Dementia with Parkinsonism linked to Chromosome 17 (FTDP-17), several mutations in the tau gene were identified showing that primary malfunction of tau can lead to neurodegeneration. Such findings shed new light on the role of post-translational modifications of tau protein occurring in other tauopathies (such as AD), including aberrant proteolysis. In AD, tau protein aggregates in intraneuronal deposits known as "neurofibrillary tangles" (NFT), one of the two hallmarks of the disease. Tau molecules normally associate to microtubules (major cytoskeletal structures); in AD, tau proteins dissociate from microtubules and aggregate into NFTs.

Inappropriate neuronal apoptosis (or neuronal cell death) is present in AD, as well as in other neurodegenerative diseases. In a previous study, the authors showed that tau is a substrate for the apoptotic protease caspase-3 (an enzyme involved in cell death processes) and an effector of apoptosis itself, in established cell lines. Moreover, the cleavage of tau by caspase-3 has been recently confirmed to occur "in vivo" in AD brain as an early event. The study shows the apoptotic properties of tau fragments in cultured hippocampal neurons, a neuronal subpopulation precociously affected by AD pathology.

According to the authors, neurodegeneration would be perpetuated by an "autocatalytic process" in which any modest proapoptotic stimulus (activating caspase-3) would promote tau cleavage generating the proapoptotic fragments. The authors also show that this effect is significantly potentiated by incubation with the amyloid peptide A-beta 25-35, a peptide included in the A-beta fragment (the constituent of extraneuronal senile plaques, another hallmark of the disease). One of the intersections between amyloid and neurofibrillary pathological pathways in AD might rely on caspase-3 cleavage of tau. Intriguingly, the authors find that one of the tau mutations described in FTDP-17, potentiates the apoptotic capacity of tau fragments; such finding has no relevance in understanding the molecular pathogenesis of FTDP-17. However, since the mutation is located in a region important for the affinity to microtubules, this observation suggests that this region is likely to be involved in the apoptotic properties of tau. These results are of general interest, since they provide insights into the pathogenetic mechanism of AD.


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The above story is based on materials provided by International School For Advanced Studies In Trieste. Note: Materials may be edited for content and length.


Cite This Page:

International School For Advanced Studies In Trieste. "Neuronal Death And Processing Of Tau Protein In Alzheimer's Disease." ScienceDaily. ScienceDaily, 1 April 2005. <www.sciencedaily.com/releases/2005/03/050329135203.htm>.
International School For Advanced Studies In Trieste. (2005, April 1). Neuronal Death And Processing Of Tau Protein In Alzheimer's Disease. ScienceDaily. Retrieved October 23, 2014 from www.sciencedaily.com/releases/2005/03/050329135203.htm
International School For Advanced Studies In Trieste. "Neuronal Death And Processing Of Tau Protein In Alzheimer's Disease." ScienceDaily. www.sciencedaily.com/releases/2005/03/050329135203.htm (accessed October 23, 2014).

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