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The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics.

Pritchard SM, Dolan PJ, Vitkus A, Johnson GV - J. Cell. Mol. Med. (2011)

Bottom Line: It has been almost 25 years since the initial discovery that tau was the primary component of the neurofibrillary tangles (NFTs) in Alzheimer disease (AD) brain.Although AD is defined by both β-amyloid (Aβ) pathology (Aβ plaques) and tau pathology (NFTs), whether or not tau played a critical role in disease pathogenesis was a subject of discussion for many years.We conclude by discussing possible avenues for therapeutic intervention based on these emerging themes of tau's role in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and the Interdepartmental Graduate Program in Neuroscience, University of Rochester, Rochester, NY, USA.

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Related in: MedlinePlus

Treatment strategies to reduce the impact of tau pathology. (A) In vitro, the formation of tau oligomers and aggregates is disrupted by the use of phenothiazine derivatives such as methylene blue. This results in a reduction of phosphorylated and total tau levels, though in vivo the effect of methylene blue treatment on the formation of aggregates is debated (see text). (B) Active immunization of tau in in vivo models has been shown to improve behavioural measures and reduce levels of phosphorylated and total tau. (C) Activators of autophagy have been shown to increase the degradation of pathological forms of tau, and improve pathological measures in mouse models of AD. (D) The detrimental effects of expressing pathological forms of tau on mitochondrial function may be slowed or reversed with antioxidants such as mitoQ, ubiquinone and other antioxidants.
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fig02: Treatment strategies to reduce the impact of tau pathology. (A) In vitro, the formation of tau oligomers and aggregates is disrupted by the use of phenothiazine derivatives such as methylene blue. This results in a reduction of phosphorylated and total tau levels, though in vivo the effect of methylene blue treatment on the formation of aggregates is debated (see text). (B) Active immunization of tau in in vivo models has been shown to improve behavioural measures and reduce levels of phosphorylated and total tau. (C) Activators of autophagy have been shown to increase the degradation of pathological forms of tau, and improve pathological measures in mouse models of AD. (D) The detrimental effects of expressing pathological forms of tau on mitochondrial function may be slowed or reversed with antioxidants such as mitoQ, ubiquinone and other antioxidants.

Mentions: Studies over the past decade have brought about a maturation of our understanding of the role of tau in AD pathogenesis. These discoveries have breathed new life into a number of encouraging avenues for future tau research including: (1) investigation of soluble, non-aggregated forms of tau as a primary disease agent, (2) exploring the role of tau as an enhancer, or even gatekeeper, of Aβ-induced degeneration, (3) elucidating the mechanisms/pathways regulating the degradation of tau as determined by its post-translational state and (4) examining the mechanisms by which pathological forms of tau may negatively impact mitochondrial biology. Going forward, studies focused in these areas as well as further mechanistic dissection of the contribution of different tau isoforms in the disease process, will provide us with foundational information for the development of therapies for the treatment of AD. Figure 2 provides a summary of possible tau-directed therapeutic strategies.


The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics.

Pritchard SM, Dolan PJ, Vitkus A, Johnson GV - J. Cell. Mol. Med. (2011)

Treatment strategies to reduce the impact of tau pathology. (A) In vitro, the formation of tau oligomers and aggregates is disrupted by the use of phenothiazine derivatives such as methylene blue. This results in a reduction of phosphorylated and total tau levels, though in vivo the effect of methylene blue treatment on the formation of aggregates is debated (see text). (B) Active immunization of tau in in vivo models has been shown to improve behavioural measures and reduce levels of phosphorylated and total tau. (C) Activators of autophagy have been shown to increase the degradation of pathological forms of tau, and improve pathological measures in mouse models of AD. (D) The detrimental effects of expressing pathological forms of tau on mitochondrial function may be slowed or reversed with antioxidants such as mitoQ, ubiquinone and other antioxidants.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4373356&req=5

fig02: Treatment strategies to reduce the impact of tau pathology. (A) In vitro, the formation of tau oligomers and aggregates is disrupted by the use of phenothiazine derivatives such as methylene blue. This results in a reduction of phosphorylated and total tau levels, though in vivo the effect of methylene blue treatment on the formation of aggregates is debated (see text). (B) Active immunization of tau in in vivo models has been shown to improve behavioural measures and reduce levels of phosphorylated and total tau. (C) Activators of autophagy have been shown to increase the degradation of pathological forms of tau, and improve pathological measures in mouse models of AD. (D) The detrimental effects of expressing pathological forms of tau on mitochondrial function may be slowed or reversed with antioxidants such as mitoQ, ubiquinone and other antioxidants.
Mentions: Studies over the past decade have brought about a maturation of our understanding of the role of tau in AD pathogenesis. These discoveries have breathed new life into a number of encouraging avenues for future tau research including: (1) investigation of soluble, non-aggregated forms of tau as a primary disease agent, (2) exploring the role of tau as an enhancer, or even gatekeeper, of Aβ-induced degeneration, (3) elucidating the mechanisms/pathways regulating the degradation of tau as determined by its post-translational state and (4) examining the mechanisms by which pathological forms of tau may negatively impact mitochondrial biology. Going forward, studies focused in these areas as well as further mechanistic dissection of the contribution of different tau isoforms in the disease process, will provide us with foundational information for the development of therapies for the treatment of AD. Figure 2 provides a summary of possible tau-directed therapeutic strategies.

Bottom Line: It has been almost 25 years since the initial discovery that tau was the primary component of the neurofibrillary tangles (NFTs) in Alzheimer disease (AD) brain.Although AD is defined by both β-amyloid (Aβ) pathology (Aβ plaques) and tau pathology (NFTs), whether or not tau played a critical role in disease pathogenesis was a subject of discussion for many years.We conclude by discussing possible avenues for therapeutic intervention based on these emerging themes of tau's role in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and the Interdepartmental Graduate Program in Neuroscience, University of Rochester, Rochester, NY, USA.

Show MeSH
Related in: MedlinePlus