Related Taxanes Research Articles

Enhancement of taxane production in cell suspension culture of Corylus avellana L. Kalınkara by elicitation and precursor feeding

Paclitaxel (trademark Taxol®) is the most effective chemotherapeutic agent against a wide range of cancers. Hazelnut (Corylus avellana L.) cell culture is a promising and inexpensive strategy for producing paclitaxel and related taxanes. This study evaluated the effect of elicitation and taxane precursor feeding for the enhancement of taxanes in a Turkish hazelnut (C. avellana cv. ‘Kalınkara’) cell suspension culture. Elicitor methyl jasmonate (100, 200 and 300 µmol L−1) and precursor phenylalanine (3μmol, 3 and 6 mmol L−1) were tested in cell suspension cultures. While methyl jasmonate increased the accumulation of taxanes, especially cephalomannine, via induction of the paclitaxel biosynthetic pathway, phenylalanine slightly induced the conversion of 10-deacetylbaccatin III and baccatin III to the end product paclitaxel (0.5349 µg g−1). The results showed that 200 µmol L−1 methyl jasmonate led to significantly greater induction of taxanes than 100 and 300 µmol L−1. The amount of cephalomannine (331.6 µg g−1) in cell suspension cultures elicited by 200 µmol L−1 methyl jasmonate was 8-fold higher than that in the control (41.61 µg g−1), while 10-deacetylbaccatin III (6.174 µg g−1) and baccatin III (3.956 µg g−1) increased almost twice as much as the control. The highest total paclitaxel yield was 5.453 µg g−1 in the same culture conditions. In conclusion, cell culture systems of C. avellana L. cv. ‘Kalınkara’ hazelnut, established for the first time, may become a potential candidate for industrial-level production of cephalomannine and other taxanes with further optimization.

Polyploidy as a strategy to increase taxane production in yew cell cultures: Obtaining and characterizing a Taxus baccata tetraploid cell line

Novel approaches to optimize the production of plant specialized metabolites are crucial to reach maximum productivity of plant biofactories. Plant polyploidization frequently enhances protein synthesis and thereby increases the biosynthesis of specialized metabolites. Paclitaxel is a valuable anticancer agent scarcely produced in nature. Therefore, plant biofactories represent a sustainable alternative source of this compound and related taxanes. With the aim of improving the productivity of Taxus spp. cell cultures, we induced polyploidy in vitro by treating immature embryos of Taxus baccata with colchicine. To obtain the polyploid cell lines, calli were induced from T. baccata plantlets previously treated with colchicine and ploidy levels were accurately identified using flow cytometry. In terms of cell morphology, tetraploid cells were about 3-fold bigger than the diploid cells. The expression of taxane pathway genes was higher in the tetraploid cell line compared to the diploid cells. Moreover, taxane production was 6.2-fold higher and the production peak was achieved 8 days earlier than in the diploid cell line, indicating a higher productivity. The obtained tetraploid cell line proved to be highly productive, constituting a step forward towards the development of a bio-sustainable production system for this chemotherapeutic drug.

Insights into the control of taxane metabolism: Molecular, cellular, and metabolic changes induced by elicitation in Taxus baccata cell suspensions.

More knowledge is needed about the molecular/cellular control of paclitaxel (PTX) production in Taxus spp. cell cultures. In this study, the yield of this anticancer agent in Taxus baccata cell suspensions was improved 11-fold after elicitation with coronatine (COR) compared to the untreated cells, and 18-fold when co-supplemented with methyl-β-cyclodextrins (β-CDs). In the dual treatment, the release of taxanes from the producer cells was greatly enhanced, with 81.6% of the total taxane content being found in the medium at the end of the experiment. The experimental conditions that caused the highest PTX production also induced its maximum excretion, and increased the expression of taxane biosynthetic genes, especially the flux-limiting BAPT and DBTNBT. The application of COR, which activates PTX biosynthesis, together with β - CDs, which form inclusion complexes with PTX and related taxanes, is evidently an efficient strategy for enhancing PTX production and release to the culture medium. Due to the recently described role of lipid droplets (LDs) in the trafficking and accumulation of hydrophobic taxanes in Taxus spp. cell cultures, the structure, number and taxane storage capacity of these organelles was also studied. In elicited cultures, the number of LDs increased and they mainly accumulated taxanes with a side chain, especially PTX. Thus, PTX constituted up to 50-70% of the total taxanes found in LDs throughout the experiment in the COR + β - CD-treated cultures. These results confirm that LDs can store taxanes and distribute them inside and outside cells.

Taxol from Corylus avellana: paving the way for a new source of this anti-cancer drug

Taxol is amongst the most effective anti-cancer drugs available in market. The increasing demand of this compound due to its use in treating wide range of cancers, as well as its high cost have triggered efforts to find alternative ways to obtain this drug. Hazel (Corylus avellana), which is already cultivated for nutritional aspects, is now attracting attention for its phytochemical content. Notably the discovery of taxol and related taxanes in this plant species prompted extensive interest to explore biotechnological production of these compounds using in vitro cultures of C. avellana. This review emphasizes the potential of C. avellana cells for production of taxol and related taxanes. The botanical description of C. avellana, its pharmacological uses and various biotechnological approaches, such as micropropagation, cell culture and genetic engineering to increase the production of taxol and related taxanes are discussed. To present an overall overview, the experience of researchers working on these aspects is mentioned and major highlights or discoveries are presented. A review of the literature suggests that C. avellana may act as a commercial and alternative source for taxol production in an eco-friendly way, which will meet the ever-increasing demand, and also help reducing the cost of this anti-cancer compound.

A systematic approach to expound the variations in taxane production under different dissolved oxygen conditions in Taxus chinensis cells.

Our results provide an evidence that the changes in taxane production caused by dissolved oxygen shifts could be associated with the global variations in the cell central carbon metabolism. Taxol is an important taxane synthesized by the Taxus plant. A two-stage culture of Taxus in vitro has been considered as an attractive alternative approach to produce Taxol and its precursors. To investigate the consequences of dissolved oxygen (DO) shifts for cell primary and secondary metabolism, we conducted metabolomic and transcriptomic profiling analyses under low dissolved oxygen (LDO), medium dissolved oxygen (MDO), and high dissolved oxygen (HDO) conditions in a suspension culture of Taxus chinensis cells. Under LDO, the results indicate a significant increase in the production of Taxol and its main precursors by 3.4- to 1.4-fold compared with those under MDO and HDO on 9th day. Multiple acyl taxanes (MAT) are abundant taxanes in the cells, and exhibited only a slight increase under the same conditions. Metabolomic analysis based on 209 primary metabolites indicated that several pathways in central carbon metabolism were involved, including the enhancement of the glycolysis pathway of glucose-6-phosphate to fructose-6-phosphate and pyruvate and the mevalonate pathway of terpene biosynthesis, and decline in the tricarboxylic acid pathway under LDO. These results indicate the mechanism by which related taxanes accumulate through enhancing the supplies of substrates and expression levels of hydroxylases. Excess acetyl-CoA supply induced by high oxygen stress was found to be correlated with high productivity of MAT. Our results provide an evidence that the changes in taxane production caused by DO shifts could be associated with the global variations in the cell central carbon metabolism.

New taxane biosynthetic gene encoding a β-phenylalanine-CoA ligase identified in jasmonate-elicited Taxus cells

The data-generating power of “omics” technologies is increasingly being harnessed in studies of plant biology to shed light on aspects such as metabolite production patterns, gene sequences and protein expression. Taxol and related taxanes, produced by several Taxus species, are high-value secondary metabolites widely used in cancer therapy due to their antineoplastic activity. To date, several biosynthetic steps of these compounds remain undefined. After carrying out a genome-wide expression analysis of jasmonate-elicited Taxus baccata cell cultures using complementary DNA-amplified fragment length polymorphism (cDNA-AFLP), we found that the increased taxane production in the target cultures was correlated with an extensive elicitor-induced genetic reprogramming. Subsequent in silico analysis allowed us to identify 15 genes with jasmonate-induced differential expression putatively involved in five unknown steps of taxane biosynthesis. Among them, the TB768 gene and its predicted 3D structure showed a strong homology with other genes previously reported to encode acyl-CoA ligases, suggesting it was involved in the formation of the taxol lateral chain. In vitro analysis confirmed that the TB768 gene encodes an acyl-CoA ligase, localized in the cytoplasm and able to convert b-phenylalanine into its CoA ester derivative. The latter is then attached to baccatin III in one of the last steps of the taxol biosynthetic pathway. In determining that the TB768 gene encodes a cytosolic CoA ligase with an important role in the taxol biosynthetic pathway, we have corroborated that the combination of a cDNA-AFLP transcriptome profiling approach with bioinformatics analysis constitutes an efficient set of tools for the identification of new genes involved in the metabolism of valuable bioactive compounds. The newly described gene will contribute to the establishment of sustainable taxol production systems through metabolic engineering or synthetic biology approaches.

Taxane production induced by methyl jasmonate in free and immobilized cell cultures of Mexican yew (Taxus globosa Schltdl)

Taxus globosa Schltdl, the Mexican yew, represents a new source of taxanes, including taxol, baccatin III, 10-deacetylbaccatin III, 10-deacetyltaxol and cephalomannine. Due to the anticancer activity and other biological activities of these compounds, and their scarcity in nature, we initiated in vitro cultures of this species with the aim of developing a biotechnological process for obtaining taxol and related taxanes. In the current work, in a batch-type two-phase culture of T. globosa, we evaluated the effect of cell immobilization and methyl jasmonate (MeJ) elicitation in two culture media containing different plant growth regulator combinations: 2,4-dichlorophenoxyacetic + benzylaminopurine (Treatment 1: T1) and picloram + kinetin (Treatment 2: T2). The productivity and excretion rate into the culture medium of baccatin III (12.79 μg L−1 d−1) (84 %), 10-deacetylbaccatin III (15 μg L−1 d−1) (0 %), 10-deacetyltaxol (3.18 μg L−1 d−1) (63 %), and cephalomannine (49.27 μg L−1 d−1) (9 %) were increased by the effect of T1 in the free cell cultures elicited with MeJ. Cell immobilization in alginate beads did not improve the biotechnological production of these four taxanes. In contrast, the highest productivity of taxol (53 μg L−1 d−1) was achieved in MeJ-elicited free cells under T2 and cell immobilization in these conditions increased productivity by more than twofold (130.35 μg L−1 d−1).

Assessing factors that affect the growth of Corylus avellana cell suspension cultures: a statistical approach

The detection of taxol and related taxanes in Corylus avellana has generated considerable interest, particularly for in vitro cell cultures. Cell suspensions are a sustainable and rational option for obtaining a continuous and reliable source of secondary metabolites in large-scale processes. We therefore focused our study on the main factors that affect the growth of C. avellana cell suspensions as a key approach to improving culture productivity. In this work, calli were successfully induced from C. avellana seeds, leaves, and stems, and the efficiency of different sterilization methods was analyzed. The effects of the basal medium, carbon source, and the type and quantity of plant growth regulators on culture growth were studied. A fractional factorial design allowed us to reduce the number of experiments and analyze all the combinations in one run, thereby reducing time, variability, and costs. Statistical analysis (ANOVA) revealed that 1-naphthaleneacetic acid (NAA) and sucrose are mandatory for the growth of C. avellana cell suspension cultures, with no interactions detected between the parameters analyzed, while growth did not depend on the addition of cytokinins. The secondary metabolism was not inhibited, detecting 1175.45 ng/L of baccatin III and traces of taxol, deacetyltaxol, and cephalomannine. Additionally, prompted by the high growth rate of the C. avellana calli, we assayed a new cold-temperature-based method to maintain a stock of calli using half-strength Murashige and Skoog solid medium, concluding that up to 5 mo at 4°C is optimal to ensure white friable calli upon regrowth at 25°C.

Induction, Growth and Paclitaxel Content of Needle-and Petiole-Derived Calli in Himalayan Yew (Taxus Wallichiana Zucc.) Under Light-Emitting Diodes

Abstract To achieve a better understanding of accumulation of paclitaxel and related taxanes in Himalayan yew (Taxus wallichiana Zucc.) callus mass, induction and growth of calli from needles and petioles under light-emitting diodes (LEDs) and production of paclitaxel and baccatin were investigated. Calli were induced from needles and petioles on Gamborg's B5 medium supplemented with 1 mg·l-1 kinetin and 4 mg·l-1 2,4-D under different com-binations of blue and red LEDs. Calli were further cultured in that medium under the same lighting conditions. Callus induction from needles and petioles and growth was better under blue LEDs than under red LEDs and fluorescent light. The combinations of blue and red LEDs produced variable results. The paclitaxel content of these calli was quantified by high-performance liquid chromatography. The paclitaxel content of calli derived from needles was 0.00628% and the 10-DAB (10-Deacetylbaccatin III) content was 0.00366%. The paclitaxel content of calli derived from petioles was 0.00412%, and no 10-DAB was detected.

Preparative isolation of paclitaxel and related taxanes from cell cultures of Taxus chinensis using reversed-phase flash chromatography

In this study, paclitaxel, baccatin III, taxuyunnanine C and sinenxane C were successfully separated by reversed-phase flash chromatography on a manually packed C18 column from Taxus chinensis cell culture extract. The crude cell culture extract was first treated with Al2O3 column chromatography and then divided into two parts: fraction 1 and fraction 2. Ten milligrams of baccatin III and 19 mg of paclitaxel were obtained from 100 mg dried fraction 1. Fifty-two milligrams of taxuyunnanine C and 11 mg sinenxane C were obtained from 100 mg dried fraction 2. The purities of the four compounds were 98.02%, 98.53%, 98.93% and 98.76%, respectively. Their structures were characterised by using UV, MS and NMR. These results indicate that paclitaxel and related taxanes including baccatin III can be obtained from cell culture in a highly pure state using reversed-phase flash chromatography.

Synergistic effect of cyclodextrins and methyl jasmonate on taxane production in Taxus x media cell cultures.

Methyl jasmonate and cyclodextrins are proven effective inducers of secondary metabolism in plant cell cultures. Cyclodextrins, which are cyclic oligosaccharides, can form inclusion complexes with nonhydrophilic secondary products, thus increasing their excretion from the producer cells to the culture medium. In the present work, using a selected Taxus x media cell line cultured in a two-stage system, the relationship between taxane production and the transcript profiles of several genes involved in taxol metabolism was studied to gain more insight into the mechanism by which these two elicitors regulate the biosynthesis and excretion of taxol and related taxanes. Gene expression was not clearly enhanced by the presence of cyclodextrins in the culture medium and variably induced by methyl jasmonate, but when the culture was supplemented with both elicitors, a synergistic effect on transcript accumulation was observed. The BAPT and DBTNBT genes, which encode the last two transferases involved in the taxol pathway, appeared to control limiting biosynthetic steps. In the cell cultures treated with both elicitors, the produced taxanes were found mainly in the culture medium, which limited retroinhibition processes and taxane toxicity for the producer cells. The expression level of a putative ABC gene was found to have increased, suggesting it played a role in the taxane excretion. Taxol biosynthesis was clearly increased by the joint action of methyl jasmonate and cyclodextrins, reaching production levels 55 times higher than in nonelicited cultures.

Seasonal Change of Contents of Six Taxanes in Branches and Leaves of Taxus chinensis var. mairei

Taxol is a natural anticancer agent mainly extracted from Taxus species. Taxanes are the precursors or branches of taxol metabolites,also have the potential for developing as anti-tumor drugs. The seasonal change of contents of six taxanes i. e. taxol,10-deacetylbaccatin Ⅲ( 10-DAB),7-xylosyl-10-deacetyl-taxol( 7-xyl-10-DAT),10-deacetyltaxol( 10-DAT),cephalomannine( CE) and 7-epi-10-deacetyl taxol( 7-epi-10-DAT) in the branches and leaves of Taxus chinensis var. mairei was studied by high Performance liquid chromatography( HPLC) method. The results showed that the contents of Taxol and 10-DAT were the lowest in August and September,at the same time the contents of 10-DAB and 7-xyl-10-DAT were relatively higher. The seasonal content change of taxol was negatively correlated with 10-DAB,and positively correlated with CE. The seasonal content change of 7-xyl-10-DAT was positively correlated with 10-DAB and 10-DAT,respectively. This paper provided the theory bases for the metabolism and accumulation rules of taxol and related taxanes,it is not only helpful to clarify the biosynthesis key steps and physiological regulation mechanisms of taxol,but also has the guidance significance for Taxus resources development.

Squalestatin-induced production of taxol and baccatin in cell suspension culture of yew (Taxus baccata L.)

Various elicitors have already been reported to enhance the production of taxol and related taxanes. In this study, effects of a fungal metabolite, squalestatin, on production of taxol and baccatin III were studied. Expressions of 4 key involved genes, ts, dbat, bapt, and dbtnbt, in suspension cultures of Taxus baccata were also detected using qPCR. Results showed that application of squalestatin significantly increased taxol and baccatin III yields. Increased expressions of the genes were in accordance with measures of taxol and baccatin accumulations in cells and medium. Production of H_{2}O_{2} has significant positive correlations with both gene expression and taxanes, indicating that the increase in H_{2}O_{2} might be involved in the upregulation of the taxane production in yew under squalestatin treatment. Our results suggest that H_{2}O_{2} is a key signaling component in the stimulation of taxane production in T. baccata cells induced by squalestatin.

Getting to the bottom of Taxol biosynthesis by fungi

Taxol (paclitaxel) is a highly-oxygenated diterpenoid natural product first isolated from the pacific yew tree (Taxus brevifolia). It is one of the most widely used anticancer drugs. Soon after the discovery of its unique mode of action and the resulting high demand, an extensive search was initiated for alternative sources to replace the slow-growing and scarce pacific yew. Thus far, however, Taxol and related compounds have only been found in the genus Taxus, which comprises a small number of slow-growing plants with a broad but generally isolated geographical distribution. In 1993, Stierle and colleagues reported the independent biosynthesis of Taxol in an endophytic fungus isolated from Taxus brevifolia, which resulted in more than 160 subsequent publications and patents addressing the biosynthesis of Taxol and related taxanes by microorganisms. The literature on fungal taxane synthesis contains numerous inconsistencies, prompting us to thoroughly re-examine Taxol biosynthesis in endophytic fungi associated with Taxus spp. Using a combination of phytochemistry, molecular biology and genome sequencing, we were unable to find any evidence for independent taxane biosynthesis in any of the endophytes, including the isolate described in the original publication (Taxomyces andreanae) and several more recent isolates from Taxus trees. Our findings therefore resolve a long-standing mystery concerning the evolution of a complex terpenoid biosynthetic pathway in two distantly-related organisms.

Coronatine, a more powerful elicitor for inducing taxane biosynthesis in Taxus media cell cultures than methyl jasmonate

Coronatine is a toxin produced by the pathogen Pseudomonas syringae. This compound has received much attention recently for its potential to act as a plant growth regulator and elicitor of plant secondary metabolism. To gain more insight into the mechanism by which elicitors can affect the biosynthesis of paclitaxel (Px) and related taxanes, the effect of coronatine (Cor) and methyl jasmonate (MeJA) on Taxus media cell cultures has been studied. For this study, a two-stage cell culture was established, in which cells were first cultured for 14 days in a medium optimised for growth, after which the cells were transferred to medium optimised for secondary metabolite production. The two elicitors were added to the medium at the beginning of the second stage. Total taxane production in the cell suspension was significantly enhanced by both elicitors, increasing from a maximum level of 8.14mg/L in control conditions to 21.48mg/L (day 12) with MeJA and 77.46mg/L (day 16) with Cor. Expression analysis indicated that the txs, t13oh, t2oh, t7oh, dbat, pam, bata and dbtnbt genes were variably induced by the presence of the elicitors. Genes encoding enzymes involved in the formation of the polihydroxylated hypothetical intermediate (TXS, T13OH, T2OH, T7OH) and the phenylalanoil CoA chain (PAM) were stronger induced than those encoding enzymes catalysing the last steps of the Px biosynthetic pathway (DBAT, BAPT and DBTNBT). Notably, although taxane accumulation differed qualitatively and quantitatively following MeJA- or Cor-elicitation, gene expression induction patterns were similar, inferring that both elicitors may involve distinct but yet uncharacterised regulatory mechanisms.

A new endophytic taxol- and baccatin III-producing fungus isolated from Taxus chinensis var. mairei

120 endophytic fungi were isolated from the old inner bark of Taxus chinensis var. mairei and only a fungus was detected to produce Taxol and related taxanes in potato dextrose agar (PDA) medium. The presence of taxol and baccatin III was confirmed by high performance liquid chromatography combined with mass spectrometry (LC-MS) and competitive inhibition enzyme immunoassay (CIEIA). The fungal compound showed cytotoxic activity on liver cancer cell line BEL7402 in vitro. The strain was identified as one of Didymostilbe sp. (designated as DF110) according to its morphological characteristics. The isolation of such fungi provided a promising alternative approach to producing taxol in the near future. Key words : Taxol, baccatin III, endophytic fungus, Didymostilbe sp.

Stromal targeted therapy in bone metastatic prostate cancer: promise delivered

Stromal targeted therapy in bone metastatic prostate cancer: promise delivered

Changes of taxane production and gene expression during the development of in vitro Taxus plant cultures

The production and accumulation of secondary metabolites in plants is always regulated by the expression of genes involved in their biosynthesis. There are very few reports about the regulation of the biosynthesis of the anticancer agent taxol and other related taxanes and the rate-limiting steps involved, especially during the development of Taxus plants. Using Taxus baccata L. plantlets grown in vitro for 1 year, our group has studied the relationship between the profile and production of taxanes and the expression of genes codifying for enzymes that participate in early and late steps of taxane biosynthesis (TXS, DBAT, BAPT and DBTNBT). A far higher taxane content was observed in the aerial part of the plantlets than in the roots, 10-deacetylbaccatin III being the most abundant taxane, with very low conversion to baccatin III and taxol. The mRNA accumulation of the studied genes was also higher in the aerial part than in the corresponding roots. Our results indicate that the low taxane levels in the roots could reflect the low transcript accumulation of the aforementioned genes in this part of the plant, although an active metabolism or translocation of taxanes to the aerial part could also be responsible. The high content of 10-deacetylbaccatin III and very low levels of baccatin III, together with the low mRNA accumulation of DBAT in the aerial part, suggest that this gene could control a limiting step in the taxane biosynthetic pathway in T. baccata plantlets grown for 1 year in in vitro conditions.

The relationship between TXS, DBAT, BAPT and DBTNBT gene expression and taxane production during the development of Taxus baccata plantlets

Taxol and related taxane accumulation in plants is regulated by the expression of genes involved in their biosynthesis. Although the metabolic pathway leading to taxol has been almost completely elucidated, comparatively little is known about the rate-limiting steps and their regulation. In this paper we report on a study of taxane production in Taxus baccata plantlets grown in vitro for 1 year. The relationship between taxane patterns and the expression of genes encoding the enzymes taxadiene synthase (TXS), 10-deacetylbaccatin III-10β- O-acetyltransferase (DBAT), baccatin III 13- O-(3-amino-3-phenylpropanoyl) transferase (BAPT) and 3′-N-debenzoyl-2′-deoxytaxol-N-benzoyltransferase (DBTNBT), involved in early and late steps of the taxane pathway, has been considered. A far higher content was found in the aerial part of the plantlets than in the roots. The most abundant taxane in the aerial parts was 10-deacetylbaccatin III, which increased as the plantlets grew, indicating a low conversion to baccatin III and taxol. In contrast, the levels of 10-deacetylbaccatin III in the roots remained lower than those of taxol. These results correlated with transcript accumulation of the studied genes, since in the aerial parts the expression of DBAT, which codes for the enzyme that converts 10-deacetylbaccatin III into baccatin III, did not increase with the age of plantlets, unlike that of TXS, BAPT and DBTNBT, suggesting that this gene controls a rate-limiting step in the taxane biosynthetic pathway. The lower taxane levels found in the roots also correlated with gene expression, since only the early pathway gene TXS was induced in this organ during the 1-year growth period.

Epothilone D Improves Microtubule Density, Axonal Integrity, and Cognition in a Transgenic Mouse Model of Tauopathy

Neurons in the brains of those with Alzheimer's disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles comprised of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, a possible therapeutic strategy for AD and related "tauopathies" is treatment with a MT-stabilizing anti-cancer drug such as paclitaxel. However, paclitaxel and related taxanes have poor blood-brain barrier permeability and thus are unsuitable for diseases of the brain. We demonstrate here that the MT-stabilizing agent, epothilone D (EpoD), is brain-penetrant and we subsequently evaluated whether EpoD can compensate for tau loss-of-function in PS19 tau transgenic mice that develop forebrain tau inclusions, axonal degeneration and MT deficits. Treatment of 3-month-old male PS19 mice with low doses of EpoD once weekly for a 3 month period significantly improved CNS MT density and axonal integrity without inducing notable side-effects. Moreover, EpoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs.