Exploring the Efficacy of Anti-amyloid-β Therapeutics in Treating Alzheimer Disease

Alzheimer Disease (AD) is the most prevalent cause of dementia, characterized by initial memory impairment and progressive cognitive decline. The exact cause of AD is not yet completely understood. However, the presence of neurotoxic amyloid-beta (Aβ) peptides in the brain is often cited as the main causative agent in AD pathogenesis. In accordance with the amyloid hypothesis, Aβ accumulation initially occurs 15-20 years prior to the development of clinical symptoms. Current therapies focus on the prodromal and preclinical stages of AD due to past treatment failures involving patients with mild to moderate AD. Passive immunization via exogenous monoclonal antibodies (mAbs) administration has emerged as a promising anti-Aβ treatment in AD. This is reinforced by the recent approval of the mAb, aducanumab. mAbs have differential selectivity in their epitopes, each recognising different conformations of Aβ. In this way, various Aβ accumulative species can be targeted. mAbs directed against Aβ oligomers, the most neurotoxic species, are producing encouraging clinical results. Through understanding the process by which mAbs target the amyloid cascade, therapeutics could be developed to clear Aβ, prevent its aggregation, or reduce its production. This review examines the clinical efficacy evidence from previous clinical trials with anti-Aβ therapeutics, in particular, the mAbs. Future therapies are expected to involve a combined-targeted approach to the multiple mechanisms of the amyloid cascade in a particular stage or disease phenotype. Additional studies of presymptomatic AD will likely join ongoing prevention trials, in which mAbs will continue to serve as the focal point.

Social experience dependent plasticity of mouse song selectivity without that of song components

Syllable sequences in male mouse ultrasonic-vocalizations (USVs), songs, contain structure - quantified through predictability, like birdsong and aspects of speech. Apparent USV innateness and lack of learnability, discount mouse USVs for modelling speech-like social communication and its deficits. Informative contextual natural sequences (SN) were theoretically extracted and they were preferred by female mice. Primary auditory cortex (A1) supragranular neurons show differential selectivity to the same syllables in SN and random sequences (SR). Excitatory neurons (EXNs) in females showed increases in selectivity to whole SNs over SRs based on extent of social exposure with male, but syllable selectivity remained unchanged. Thus mouse A1 single neurons adaptively represent entire order of acoustic units without altering selectivity of individual units, fundamental to speech perception. Additionally, observed plasticity was replicated with silencing of somatostatin positive neurons, which had plastic effects opposite to EXNs, thus pointing out possible pathways involved in perception of sound sequences.

Electrical Conductivity and Ion Exchange Properties of Polyaniline Antimony Tin Tung state Nano composite

The nano composite, polyaniline antimony tin tungstate in the H+ form was synthesized by a simple general method. EDS and ICP- AES methods were used to find the chemical constitution of the material. Further characterizations were done by TGA, XRD analysis, FTIR Spectroscopic analysis, UV-Visible DRS studies to find the optical properties, SEM for finding surface morphology, etc. Size determination using XRD peaks and TEM images confirmed its nano size. Investigation on ion exchange capacity and distribution coefficients for many metal ions revealed the ion exchange character. The composite exhibited differential selectivity forheavy metal ions such as PbII, ThIV, HgIV, etc. which are important in environmental applications like separation and treatment of polluted water from these metal ions. The electrical properties studied by Four–probe method revealed a high conductivity of 0.42 S/cm at room temperature and it decreases with an increase in temperature. These results suggest various applications of this nano compositein optoelectronics.

Carbon dioxide transport across membranes

Carbon dioxide (CO 2 ) movement across cellular membranes is passive and governed by Fick's law of diffusion. Until recently, we believed that gases cross biological membranes exclusively by dissolving in and then diffusing through membrane lipid. However, the observation that some membranes are CO 2 impermeable led to the discovery of a gas molecule moving through a channel; namely, CO 2 diffusion through aquaporin-1 (AQP1). Later work demonstrated CO 2 diffusion through rhesus (Rh) proteins and NH 3 diffusion through both AQPs and Rh proteins. The tetrameric AQPs exhibit differential selectivity for CO 2 versus NH 3 versus H 2 O, reflecting physico-chemical differences among the small molecules as well as among the hydrophilic monomeric pores and hydrophobic central pores of various AQPs. Preliminary work suggests that NH 3 moves through the monomeric pores of AQP1, whereas CO 2 moves through both monomeric and central pores. Initial work on AQP5 indicates that it is possible to create a metal-binding site on the central pore's extracellular face, thereby blocking CO 2 movement. The trimeric Rh proteins have monomers with hydrophilic pores surrounding a hydrophobic central pore. Preliminary work on the bacterial Rh homologue AmtB suggests that gas can diffuse through the central pore and three sets of interfacial clefts between monomers. Finally, initial work indicates that CO 2 diffuses through the electrogenic Na/HCO 3 cotransporter NBCe1. At least in some cells, CO 2 -permeable proteins could provide important pathways for transmembrane CO 2 movements. Such pathways could be amenable to cellular regulation and could become valuable drug targets.

Dissecting the molecular determinants of clinical PARP1 inhibitor selectivity for tankyrase1

Poly ADP ribosyltransferases play a critical role in DNA repair and cell death, and PARP1 is a particularly important therapeutic target for the treatment of breast cancer due to its synthetic lethal relationship with BRCA1/2. Numerous PARP1 inhibitors have been developed, and their efficacy in cancer treatment is attributed to both the inhibition of enzymatic activity and their ability to trap PARP1 on to the damaged DNA, which is cytotoxic. Of the clinical PARP inhibitors, talazoparib is the most effective at trapping PARP1 on damaged DNA. Biochemically, talazoparib is also suspected to be a potent inhibitor of PARP5a/b (tankyrase1/2), which is an important regulator of Wnt/β-catenin pathway. Here we show using competition experiments in cell lysate that, at a clinically relevant concentration, talazoparib can potentially bind and engage tankyrase1. Using surface plasmon resonance, we measured the dissociation constants of talazoparib, olaparib, niraparib and veliparib for their interaction with PARP1 and tankyrase1. The results show that talazoparib has strong affinity for PARP1 as well as uniquely strong affinity for tankyrase1. Finally, we used crystallography and hydrogen deuterium exchange mass spectroscopy to dissect the molecular mechanism of differential selectivity of these PARP1 inhibitors. From these data, we conclude that subtle differences between the ligand binding sites of PARP1 and tankyrase1, differences in the electrostatic nature of the ligands, protein dynamics, and ligand conformational energetics contribute to the different pharmacology of these PARP1 inhibitors. These results will help in the design of drugs to treat Wnt-β-catenin pathway-related cancers, such as colorectal cancers.

An Appetite for Destruction: Detecting Prey-Selective Binding of α-Neurotoxins in the Venom of Afro-Asian Elapids

Prey-selective venoms and toxins have been documented across only a few species of snakes. The lack of research in this area has been due to the absence of suitably flexible testing platforms. In order to test more species for prey specificity of their venom, we used an innovative taxonomically flexible, high-throughput biolayer interferometry approach to ascertain the relative binding of 29 α-neurotoxic venoms from African and Asian elapid representatives (26 Naja spp., Aspidelaps scutatus, Elapsoidea boulengeri, and four locales of Ophiophagus hannah) to the alpha-1 nicotinic acetylcholine receptor orthosteric (active) site for amphibian, lizard, snake, bird, and rodent targets. Our results detected prey-selective, intraspecific, and geographical differences of α-neurotoxic binding. The results also suggest that crude venom that shows prey selectivity is likely driven by the proportions of prey-specific α-neurotoxins with differential selectivity within the crude venom. Our results also suggest that since the α-neurotoxic prey targeting does not always account for the full dietary breadth of a species, other toxin classes with a different pathophysiological function likely play an equally important role in prey immobilisation of the crude venom depending on the prey type envenomated. The use of this innovative and taxonomically flexible diverse assay in functional venom testing can be key in attempting to understanding the evolution and ecology of α-neurotoxic snake venoms, as well as opening up biochemical and pharmacological avenues to explore other venom effects.