Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice

Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).     

A Novel Locus for Ectodermal Dysplasia of Hairs, Nails and Teeth Type Maps to Chromosome 18q22.1–22.3

Ectodermal dysplasias (EDs) are developmental disorders affecting tissues of ectodermal origin including hair, nails, teeth and sweat glands. Ectodermal dysplasia of hair, nails and teeth is a rare type of congenital disorder characterized by sparse and thin hair, dystrophic finger-and toenails and missing and abnormal teeth. In an effort to understand the molecular basis of this form of ED a family of Pakistani origin with an autosomal recessive pattern of inheritance was ascertained from a remote region in Pakistan. The clinical features of the affected individuals included thin and fine hair on the scalp, dystrophic and flat nails, absent or sparse eyebrows and eyelashes, missing and abnormal teeth, and thin body hair. A human genome scan carried out using microsatellite markers mapped the disease locus in this family to chromosome 18q22.1–18q22.3. A maximum two-point LOD score of 2.73 (θ= 0.0) was obtained at marker D18S541. Multipoint linkage analysis resulted in a maximum LOD score of 3.42 obtained with several markers, including D18S1125, ATA82B02, D18S848, D18S488, D18S1091, and D18S485, which supported the linkage. The linkage interval is flanked by markers D18S857 and D18S815, which corresponds to a region of 17.32 cM according to Rutgers combined linkage and physical map (build 36). This region covers 8.63 Mb according to the sequence-based physical map. Three candidate genes, CDH7, CDH19 and ZNF407 , from the linkage interval were sequenced and found to be negative for functional sequence variants. This study is the first step towards the identification of a gene involved in hair, nails and teeth type ED.     

Progress and prospects in the management of bacterial infections and developments in Phytotherapeutic modalities

The advent of antibiotics revolutionized medical care resulting in significantly reduced mortality and morbidity caused by infectious diseases. However, excessive use of antibiotics has led to the development of antibiotic resistance and indeed, the incidence of multidrug-resistant pathogens is considered as a major disadvantage in medication strategy, which has led the scholar's attention towards innovative antibiotic sources in recent years. Medicinal plants contain a variety of secondary metabolites with a wide range of therapeutic potential against the resistant microbes. Therefore, the aim of this review is to explore the antibacterial potential of traditional herbal medicine against bacterial infections. More than 200 published research articles reporting the therapeutic potential of medicinal plants against drug-resistant microbial infections were searched using different databases such as Google Scholar, Science Direct, PubMed and the Directory of Open Access Journals (DOAJ), etc., with various keywords like medicinal plants having antibacterial activities, antimicrobial potentials, phytotherapy of bacterial infection, etc. Articles were selected related to the efficacious herbs easily available to local populations addressing common pathogens. Various plants such as Artocarpus communis, Rheum emodi, Gentiana lutea L., Cassia fistula L., Rosemarinus officinalis, Argemone maxicana L, Hydrastis canadensis, Citrus aurantifolia, Cymbopogon citrates, Carica papaya, Euphorbia hirta, etc, were found to have significant antibacterial activities. Although herbal preparations have promising potential in the treatment of multidrug-resistant bacterial infection, still more research is required to isolate phytoconstituents, their mechanism of action as well as to find their impacts on the human body.     

BDA-410: a novel synthetic calpain inhibitor active against blood stage malaria

Falcipains, the papain-family cysteine proteases of the Plasmodium falciparum, are potential drug targets for malaria parasite. Pharmacological inhibition of falcipains can block the hydrolysis of hemoglobin, parasite development, and egress, suggesting that falcipains play a key role at the blood stage of parasite life cycle. In the present study, we evaluated the anti-malarial effects of BDA-410, a novel cysteine protease inhibitor as a potential anti-malarial drug. Recombinant falcipain (MBP-FP-2B) and P. falciparum trophozoite extract containing native falcipains were used for enzyme inhibition studies in vitro. The effect of BDA-410 on the malaria parasite development in vitro as well as its anti-malarial activity in vivo was evaluated using the Plasmodium chabaudi infection rodent model. The 50% inhibitory concentrations of BDA-410 were determined to be 628 and 534nM for recombinant falcipain-2B and parasite extract, respectively. BDA-410 inhibited the malaria parasite growth in vitro with an IC(50) value of 173nM causing irreversible damage to the intracellular parasite. In vivo, the BDA-410 delayed the progression of malaria infection significantly using a mouse model of malaria pathogenesis. The characterization of BDA-410 as a potent inhibitor of P. falciparum cysteine proteases, and the demonstration of its efficacy in blocking parasite growth both in vitro and in vivo assays identifies BDA-410 is an important lead compound for the development of novel anti-malarial drugs.     

New developments in animal models of Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by deterioration in mental function leading to dementia, deposition of amyloid plaques and neurofibrillary tangles (NFTs), and neuronal loss. The major component of plaques is the amyloid-b peptide (Ab), whereas NFTs are assemblies of hyperphosphorylated forms of the microtubule-associated protein tau. Electron microscopy of NFTs reveals structures known as paired helical filaments (PHFs). In familial AD (FAD), mutations in three distinct genes drive Aβ synthesis by favoring endoproteolytic secretase cleavages that liberate Aβ from the Alzheimer b-amyloid precursor protein (APP). This suggests that excess Ab initiates a pathogenic cascade in humans that culminates in all the pathologic and cellular hallmarks of AD. Building upon the knowledge of FAD mutations, incremental technical advances have now allowed reproduceable creation of APP transgenic mice that exhibit AD-like amyloid pathology and Aβ burdens. These transgenic mouse lines also exhibit deficits in spatial reference and working memory, with immunization against Aβ abrogating both AD-associated phenotypes. Besides establishing a proof of principle for Ab-directed therapies, these findings suggest a potential to identify individual elements in the pathogenic pathway that lead to cognitive dysfunction. Furthermore, transgenic APP mice with potent amyloid deposition will likely form a beachhead to capture the final elements of AD neuropathology—cell loss and NFTs composed of PHFs—that are missing from current transgenic models.