Discovery of Compounds That Will Prevent Tau Pathology

Kosik, Kenneth S.; Ahn, Jae Suk; Stein, Ross L.; Yeh, Li-An

doi:10.1385/jmn:19:3:261

Cited by 13 publications

(15 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whether or not this promotes aggregation is a matter of debate, but if one makes that assumption it would be natural to reduce the activity of the responsible kinases (or enhance the activity of phosphatases). Thus, in current efforts to find inhibitors of tauopathy one can distinguish two approaches, screens for inhibitors of kinase signaling (52)(53)(54), and aggregation inhibitors (49). Our own experimental evidence suggests that phosphorylation in vitro does not promote tau aggregation but rather reduces it (6), and therefore we decided to search directly for aggregation inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Anthraquinones Inhibit Tau Aggregation and Dissolve Alzheimer's Paired Helical Filaments in Vitro and in Cells

Pickhardt

Gažová

Bergen

et al. 2005

Journal of Biological Chemistry

318

256

View full text Add to dashboard Cite

The abnormal aggregation of tau protein into paired helical filaments (PHFs) is one of the hallmarks of Alzheimer's disease. Aggregation takes place in the cytoplasm and could therefore be cytotoxic for neurons. To find inhibitors of PHF aggregation we screened a library of 200,000 compounds. The hits found in the PHF inhibition assay were also tested for their ability to dissolve preformed PHFs. The results were obtained using a thioflavin S fluorescence assay for the detection and quantification of tau aggregation in solution, a tryptophan fluorescence assay using tryptophan-containing mutants of tau, and confirmed by a pelleting assay and electron microscopy of the products. Here we demonstrate the feasibility of the approach with several compounds from the family of anthraquinones, including emodin, daunorubicin, adriamycin, and others. They were able to inhibit PHF formation with IC 50 values of 1-5 M and to disassemble preformed PHFs at DC 50 values of 2-4 M. The compounds had a similar activity for PHFs made from different tau isoforms and constructs. The compounds did not interfere with the stabilization of microtubules by tau. Tau-inducible neuroblastoma cells showed the formation of tau aggregates and concomitant cytotoxicity, which could be prevented by inhibitors. Thus, small molecule inhibitors could provide a basis for the development of tools for the treatment of tau pathology in AD and other tauopathies.

show abstract

Section: Discussionmentioning

confidence: 99%

Anthraquinones Inhibit Tau Aggregation and Dissolve Alzheimer's Paired Helical Filaments in Vitro and in Cells

Pickhardt

Gažová

Bergen

et al. 2005

Journal of Biological Chemistry

318

256

View full text Add to dashboard Cite

show abstract

“…A proximal pathological feature of AD is the formation of neurofibrillary tangles by the microtubule associated protein Tau (mutations in Tau cause hereditary frontotemporal dementia (1,2)). However, the amyloid precursor protein (APP) remains central to our understanding AD progression as a devastating neurodegenerative disease.…”

Section: A Metals and Alzheimer's Disease (Ad) And Parkinson's Diseamentioning

confidence: 99%

Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases

Cahill

Lahiri

Huang

et al. 2009

Biochimica et Biophysica Acta (BBA) - General Subjects

View full text Add to dashboard Cite

Summary Recent studies that alleles in the hemochromatosis gene may accelerate the onset of Alzheimer's disease (AD) by five years have validated interest in the model in which metals (particularly iron) accelerate disease course. Biochemical and biophysical measurements demonstrated the presence of elevated levels of neurotoxic copper, zinc and iron in the brains of AD patients. Intracellular levels of amyloid precursor protein (APP) holoprotein were shown to be modulated via iron by a mechanism that is similar to the translation control of the ferritin L- and H mRNAs by Iron-responsive Element (IRE) RNA stem loops in their 5′untranslated regions (5′UTRs). Recently, we reported a putative IRE-like sequence to be present in the 5′UTR of the Parkinson's disease (PD) specific alpha synuclein (ASYN) transcript. ASYN encodes the non-Aβ component (NAC) of amyloid plaques. The demonstration of iron-dependent translation of APP mRNA, the involvement of metals in the plaque of AD patients and of increased iron in striatal neurons in the Substantia nigra (SN) of PD patients, have each encouraged the development of metal attenuating agents and iron chelators as a major new therapeutic strategy for the treatment of these neurodegenerative diseases. In the case of AD, metal based therapeutics may ultimately prove more cost effective than the use of an amyloid vaccine as the preferred anti-amyloid therapeutic strategy to ameliorate the cognitive decline of AD patients.

show abstract

“…87 Most approaches to interfering with tau phosphorylation rely on inhibiting different kinases or activation of phosphatases. 88 MARK. The KXGS motifs in the repeat region of tau are phosphorylated by MARK/Par-1.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

View full text Add to dashboard Cite

Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

show abstract

Discovery of Compounds That Will Prevent Tau Pathology

Cited by 13 publications

References 56 publications

Anthraquinones Inhibit Tau Aggregation and Dissolve Alzheimer's Paired Helical Filaments in Vitro and in Cells

Anthraquinones Inhibit Tau Aggregation and Dissolve Alzheimer's Paired Helical Filaments in Vitro and in Cells

Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Contact Info

Product

Resources

About