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Formation and propagation of tau oligomeric seeds.

Gerson JE, Kayed R - Front Neurol (2013)

Bottom Line: Recently, researchers have reported the ability of tau oligomers to enter and exit cells, propagating from disease-affected regions to unaffected areas.While the mechanism by which the spreading of misfolded tau occurs has yet to be elucidated, there are a few different models which have been proposed, including cell membrane stress and pore-formation, endocytosis and exocytosis, and non-traditional secretion of protein not enclosed by a membrane.Coming to an understanding of how toxic tau species seed and spread through the brain will be crucial to finding effective treatments for neurodegenerative tauopathies.

View Article: PubMed Central - PubMed

Affiliation: George P. and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch , Galveston, TX , USA ; Department of Neurology, University of Texas Medical Branch , Galveston, TX , USA ; Department of Neuroscience and Cell Biology, University of Texas Medical Branch , Galveston, TX , USA.

ABSTRACT
Tau misfolding and aggregation leads to the formation of neurofibrillary tangles (NFTs), which have long been considered one of the main pathological hallmarks for numerous neurodegenerative diseases known as tauopathies, including Alzheimer's Disease (AD) and Parkinson's Disease (PD). However, recent studies completed both in vitro and in vivo suggest that intermediate forms of tau, known as tau oligomers, between the monomeric form and NFTs are the true toxic species in disease and the best targets for anti-tau therapies. However, the exact mechanism by which the spread of pathology occurs is unknown. Evidence suggests that tau oligomers may act as templates for the misfolding of native tau, thereby seeding the spread of the toxic forms of the protein. Recently, researchers have reported the ability of tau oligomers to enter and exit cells, propagating from disease-affected regions to unaffected areas. While the mechanism by which the spreading of misfolded tau occurs has yet to be elucidated, there are a few different models which have been proposed, including cell membrane stress and pore-formation, endocytosis and exocytosis, and non-traditional secretion of protein not enclosed by a membrane. Coming to an understanding of how toxic tau species seed and spread through the brain will be crucial to finding effective treatments for neurodegenerative tauopathies.

No MeSH data available.


Related in: MedlinePlus

Schematic illustrating the central role of tau oligomers in tauopathies. Tau intermediate soluble aggregates (tau oligomers) are the toxic tau entities and initiators of tau pathology and propagation in tauopathies, rather than monomeric tau or hyperphosphorylated NFTs (p-NFTs). Sonication of fibrillar tau generates toxic tau oligomers. Thus, tau oligomers represent the ideal target for anti-tau therapeutic approaches. AFM images are of brain-derived tau oligomers and NFT (72, 138).
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Figure 1: Schematic illustrating the central role of tau oligomers in tauopathies. Tau intermediate soluble aggregates (tau oligomers) are the toxic tau entities and initiators of tau pathology and propagation in tauopathies, rather than monomeric tau or hyperphosphorylated NFTs (p-NFTs). Sonication of fibrillar tau generates toxic tau oligomers. Thus, tau oligomers represent the ideal target for anti-tau therapeutic approaches. AFM images are of brain-derived tau oligomers and NFT (72, 138).

Mentions: Biochemical analysis of human AD brain tissue has also yielded results suggesting that tau oligomers may initiate toxicity, rather than NFTs. When compared to control brains, levels of tau oligomers were found to be significantly increased in AD brains early in the disease, prior to when NFTs appear and clinical symptoms are evident (9, 21–23). In addition to correlative evidence for the importance of tau oligomers to toxicity, treatment with tau oligomers has also been shown to cause adverse effects in animals. Isolated tau oligomers, but not monomers or NFTs, induced memory impairments, synaptic dysfunction, and mitochondrial dysfunction when given intracerebrally to wild-type mice (24). Therefore, it is possible that NFTs are actually neuroprotective, sequestering toxic forms of tau into large aggregates with less flexibility and surface area to interact with cells. All of these studies form the framework for the model of the progression of neurodegenerative tauopathies beginning with the seeding and propagation of toxic tau oligomers (Figure 1).


Formation and propagation of tau oligomeric seeds.

Gerson JE, Kayed R - Front Neurol (2013)

Schematic illustrating the central role of tau oligomers in tauopathies. Tau intermediate soluble aggregates (tau oligomers) are the toxic tau entities and initiators of tau pathology and propagation in tauopathies, rather than monomeric tau or hyperphosphorylated NFTs (p-NFTs). Sonication of fibrillar tau generates toxic tau oligomers. Thus, tau oligomers represent the ideal target for anti-tau therapeutic approaches. AFM images are of brain-derived tau oligomers and NFT (72, 138).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3713404&req=5

Figure 1: Schematic illustrating the central role of tau oligomers in tauopathies. Tau intermediate soluble aggregates (tau oligomers) are the toxic tau entities and initiators of tau pathology and propagation in tauopathies, rather than monomeric tau or hyperphosphorylated NFTs (p-NFTs). Sonication of fibrillar tau generates toxic tau oligomers. Thus, tau oligomers represent the ideal target for anti-tau therapeutic approaches. AFM images are of brain-derived tau oligomers and NFT (72, 138).
Mentions: Biochemical analysis of human AD brain tissue has also yielded results suggesting that tau oligomers may initiate toxicity, rather than NFTs. When compared to control brains, levels of tau oligomers were found to be significantly increased in AD brains early in the disease, prior to when NFTs appear and clinical symptoms are evident (9, 21–23). In addition to correlative evidence for the importance of tau oligomers to toxicity, treatment with tau oligomers has also been shown to cause adverse effects in animals. Isolated tau oligomers, but not monomers or NFTs, induced memory impairments, synaptic dysfunction, and mitochondrial dysfunction when given intracerebrally to wild-type mice (24). Therefore, it is possible that NFTs are actually neuroprotective, sequestering toxic forms of tau into large aggregates with less flexibility and surface area to interact with cells. All of these studies form the framework for the model of the progression of neurodegenerative tauopathies beginning with the seeding and propagation of toxic tau oligomers (Figure 1).

Bottom Line: Recently, researchers have reported the ability of tau oligomers to enter and exit cells, propagating from disease-affected regions to unaffected areas.While the mechanism by which the spreading of misfolded tau occurs has yet to be elucidated, there are a few different models which have been proposed, including cell membrane stress and pore-formation, endocytosis and exocytosis, and non-traditional secretion of protein not enclosed by a membrane.Coming to an understanding of how toxic tau species seed and spread through the brain will be crucial to finding effective treatments for neurodegenerative tauopathies.

View Article: PubMed Central - PubMed

Affiliation: George P. and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch , Galveston, TX , USA ; Department of Neurology, University of Texas Medical Branch , Galveston, TX , USA ; Department of Neuroscience and Cell Biology, University of Texas Medical Branch , Galveston, TX , USA.

ABSTRACT
Tau misfolding and aggregation leads to the formation of neurofibrillary tangles (NFTs), which have long been considered one of the main pathological hallmarks for numerous neurodegenerative diseases known as tauopathies, including Alzheimer's Disease (AD) and Parkinson's Disease (PD). However, recent studies completed both in vitro and in vivo suggest that intermediate forms of tau, known as tau oligomers, between the monomeric form and NFTs are the true toxic species in disease and the best targets for anti-tau therapies. However, the exact mechanism by which the spread of pathology occurs is unknown. Evidence suggests that tau oligomers may act as templates for the misfolding of native tau, thereby seeding the spread of the toxic forms of the protein. Recently, researchers have reported the ability of tau oligomers to enter and exit cells, propagating from disease-affected regions to unaffected areas. While the mechanism by which the spreading of misfolded tau occurs has yet to be elucidated, there are a few different models which have been proposed, including cell membrane stress and pore-formation, endocytosis and exocytosis, and non-traditional secretion of protein not enclosed by a membrane. Coming to an understanding of how toxic tau species seed and spread through the brain will be crucial to finding effective treatments for neurodegenerative tauopathies.

No MeSH data available.


Related in: MedlinePlus