Therapies for Alzheimer's disease

Melnikova, Irena

doi:10.1038/nrd2314

Cited by 185 publications

(112 citation statements)

References 3 publications

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“…The intranasal formulation of NAP (Chemical Abstract Service no. 211439-12-2) is currently in phase II clinical trials in an AD program initially targeting elderly patients suffering from amnestic mild cognitive impairment (Allon Therapeutics Inc., Vancouver, BC, Canada) (Melnikova, 2007).…”

Section: Discussionmentioning

confidence: 99%

A Neuronal Microtubule-Interacting Agent, NAPVSIPQ, Reduces Tau Pathology and Enhances Cognitive Function in a Mouse Model of Alzheimer's Disease

Matsuoka

Jouroukhin

Gray

et al. 2008

J Pharmacol Exp Ther

201

139

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Neurofibrillary tangles composed of aggregated, hyperphosphorylated tau in an abnormal conformation represent one of the major pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. However, recent data suggest that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles. In the earliest stages of tauopathy, tau detaches from microtubules and accumulates in the cytosol of the somatodendritic compartment of cells. Either as a cause or an effect, tau becomes hyperphosphorylated and aggregates into paired helical filaments that comprise the tangles. To assess whether an agent that modulates microtubule function can inhibit the pathogenic process and prevent cognitive deficits in a transgenic mouse model with AD-relevant tau pathology, we administered the neuronal tubulin-preferring agent, NAPVSIPQ (NAP). Three months of treatment with NAP at an early-to-moderate stage of tauopathy reduced the levels of hyperphosphorylated soluble and insoluble tau. A 6-month course of treatment improved cognitive function. Although nonspecific tubulin-interacting agents commonly used for cancer therapy are associated with adverse effects due to their antimitotic activity, no adverse effects were found after 6 months of exposure to NAP. Our results suggest that neuronal microtubule interacting agents such as NAP may be useful therapeutic agents for the treatment or prevention of tauopathies.Neurofibrillary tangles containing hyperphosphorylated tau represent one of the principal pathological hallmarks of AD. Clinical progression of AD is tightly related to tau pathology (Braak and Braak, 1995), and a recent transgenic mouse study suggests that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles (Roberson et al

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Section: Discussionmentioning

confidence: 99%

A Neuronal Microtubule-Interacting Agent, NAPVSIPQ, Reduces Tau Pathology and Enhances Cognitive Function in a Mouse Model of Alzheimer's Disease

Matsuoka

Jouroukhin

Gray

et al. 2008

J Pharmacol Exp Ther

201

139

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“…Despite the problems, progress towards human therapy has been made. Human studies have been begun with γ-secretase inhibitors [67,68].…”

Section: Therapeutic Approaches That Decrease Aβ Synthesismentioning

confidence: 99%

Impact of amyloid imaging on drug development in Alzheimer's disease

Mathis

Lopresti

Klunk

2007

Nuclear Medicine and Biology

111

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Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Aβ plaques in the brain, to help test the amyloid cascade hypothesis of AD, and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Aβ imaging agents are currently underway. We reported the first PET studies of the carbon-11-labeled thioflavin-T derivative Pittsburgh Compound B ([ 11 C]PiB) in 2004, and this work has subsequently been extended to include a variety of subject groups including AD, mild cognitive impairment (MCI), and healthy controls. The ability to quantify regional Aβ plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.

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“…Acetylcholine esterase hydrolyzes the neurotransmitter acetylcholine and is a major therapeutic target for the symptomatic treatment of Alzheimer's disease. 18 In addition, both compounds did not affect the other tested enzyme activities and did not inhibit cell proliferation.…”

Section: Biological Activitymentioning

confidence: 99%

Phenelfamycins G and H, new elfamycin-type antibiotics produced by Streptomyces albospinus Acta 3619

et al. 2011

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Phenelfamycins G and H are new members of the family of elfamycin antibiotics with the basic structure of phenelfamycins E and F, respectively, which are also well known as ganefromycins a and b. Phenelfamycins G and H differ from phenelfamycins E and F by an additional hydroxy group at position C-30, which is not described so far for any of the elfamycin-type antibiotics. The actinomycete strain that produced phenelfamycins G and H was identified to be Streptomyces albospinus based on its 16S rRNA gene sequence. Phenelfamycins G and H exhibit a narrow antibacterial spectrum with a pronounced inhibitory activity against Propionibacterium acnes. The Journal of Antibiotics (2011) 64, 257-266; doi:10.1038/ja2010.170; published online 2 February 2011 Keywords: elfamycin antibiotics; ganefromycin; phenelfamycin; Propionibacterium acnes; Streptomyces INTRODUCTIONEnvironmental samples were collected from untapped Malaysian ecological niches to isolate actinomycetes strains, which were investigated within our HPLC-diode array screening program for the production of secondary metabolites with the aim of detecting novel drugs for pharmaceutical applications. 1 Strain Acta 3619 was isolated from a soil collected from the rhizosphere of bamboo trees in the tropical rainforest of the University of Malaya Field Station at Gombak, Selangor, Malaysia. The strain was found to be of special interest, as it gave two significant peaks in the HPLC analysis of an extract of the culture filtrate having congruent UV-vis spectra that differed from all 937 reference compounds stored in our HPLC-UVvis database. 2 Structure elucidation of the two isolated compounds revealed a relationship with phenelfamycins E and F and therefore were named as phenelfamycins G (1) and H (2), respectively. Their structures are shown in Figure 1.Phenelfamycins belong to the elfamycin family of antibiotics, which inhibit protein synthesis of bacteria by an interaction with elongation factor Tu, demonstrated in prokaryotic cells. [3][4][5] Hence they derived their name from this interaction. Elfamycins can be subdivided into three types according to their structure. Type 1 includes kirromycin 6 (mocimycin), aurodox, 7,8 heneicomycin 9 and efrotomycin. 10 Type 2, elfamycin, is represented by kirrothricin with an open tetrahydrofuran ring in the aglycone. 11 Finally, type 3 contains the phenelfamycins with a phenylacetyl substitution at position C-22 or C-23 and C-33 O-glycosylation with mono-(phenelfamycins A and B), di-(phenelfamycins C and D) or trisaccharide units (phenelfamycins E and F, also named as ganefromycins a and b). 12,13 All elfamycins show a very narrow antibacterial spectrum against human pathogens and most of them show excellent activities as growth-promoting agents in animals. 14 In this paper we report on the new phenelfamycins 1 and 2, the taxonomy of the producing strain, their fermentation, isolation, structure elucidation and biological activity. RESULTS Taxonomy of the producing strainStrain Acta 3619 was isolated from the rhizosphere so...

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Therapies for Alzheimer's disease

Cited by 185 publications

References 3 publications

A Neuronal Microtubule-Interacting Agent, NAPVSIPQ, Reduces Tau Pathology and Enhances Cognitive Function in a Mouse Model of Alzheimer's Disease

A Neuronal Microtubule-Interacting Agent, NAPVSIPQ, Reduces Tau Pathology and Enhances Cognitive Function in a Mouse Model of Alzheimer's Disease

Impact of amyloid imaging on drug development in Alzheimer's disease

Phenelfamycins G and H, new elfamycin-type antibiotics produced by Streptomyces albospinus Acta 3619

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