Neuronal Toxicity of CdS Nanoparticles Prepared by Laser Ablation and their Effect on Liver

In this study, one hundred ten male white rabbits of the New Zealand type, weight (1-2) Kgm, age (12-18) month, obtained from local markets, rabbits was putted in specific cages specially made for this purpose one week before dosing, and under appropriate conditions of temperature (25-28) °C, a light period (14) hour per day. With good ventilation, the standard bush and water were provided to rabbits using aluminum containers in equal quantities. Rabbits were orally administered for two weeks with CdS nanoparticles (dose= 1ml/kg and concentration=20 μg/mL orally), after which blood was drawn from the rabbit's heart to make blood measurements and liver enzymes. Rabbits were dissected and liver was preserved with formalin for histological examination. Keywords: CdS Nanoparticles; Laser Ablation; Neuronal toxicity; Liver; Beta vulgaris L..

Soluble Amyloid-β Consumption in Alzheimer’s Disease

Brain proteins function in their soluble, native conformation and cease to function when transformed into insoluble aggregates, also known as amyloids. Biophysically, the soluble-to-insoluble phase transformation represents a process of polymerization, similar to crystallization, dependent on such extrinsic factors as concentration, pH, and a nucleation surface. The resulting cross-β conformation of the insoluble amyloid is markedly stable, making it an unlikely source of toxicity. The spread of brain amyloidosis can be fully explained by mechanisms of spontaneous or catalyzed polymerization and phase transformation instead of active replication, which is an enzyme- and energy-requiring process dependent on a specific nucleic acid code for the transfer of biological information with high fidelity. Early neuronal toxicity in Alzheimer’s disease may therefore be mediated to a greater extent by a reduction in the pool of soluble, normal-functioning protein than its accumulation in the polymerized state. This alternative loss-of-function hypothesis of pathogenicity can be examined by assessing the clinical and neuroimaging effects of administering non-aggregating peptide analogs to replace soluble amyloid-β levels above the threshold below which neuronal toxicity may occur. Correcting the depletion of soluble amyloid-β, however, would only exemplify ‘rescue medicine.’ Precision medicine will necessitate identifying the pathogenic factors catalyzing the protein aggregation in each affected individual. Only then can we stratify patients for etiology-specific treatments and launch precision medicine for Alzheimer’s disease and other neurodegenerative disorders.

Treating Neurodegenerative Disease with Antioxidants: Efficacy of the Bioactive Phenol Resveratrol and Mitochondrial-Targeted MitoQ and SkQ

Growing evidence from neurodegenerative disease research supports an early pathogenic role for mitochondrial dysfunction in affected neurons that precedes morphological and functional deficits. The resulting oxidative stress and respiratory malfunction contribute to neuronal toxicity and may enhance the vulnerability of neurons to continued assault by aggregation-prone proteins. Consequently, targeting mitochondria with antioxidant therapy may be a non-invasive, inexpensive, and viable means of strengthening neuronal health and slowing disease progression, thereby extending quality of life. We review the preclinical and clinical findings available to date of the natural bioactive phenol resveratrol and two synthetic mitochondrial-targeted antioxidants, MitoQ and SkQ.

Developmental and Neurotoxicity of Acrylamide to Zebrafish

Acrylamide is a commonly used industrial chemical that is known to be neurotoxic to mammals. However, its developmental toxicity is rarely assessed in mammalian models because of the cost and complexity involved. We used zebrafish to assess the neurotoxicity, developmental and behavioral toxicity of acrylamide. At 6 h post fertilization, zebrafish embryos were exposed to four concentrations of acrylamide (10, 30, 100, or 300 mg/L) in a medium for 114 h. Acrylamide caused developmental toxicity characterized by yolk retention, scoliosis, swim bladder deficiency, and curvature of the body. Acrylamide also impaired locomotor activity, which was measured as swimming speed and distance traveled. In addition, treatment with 100 mg/L acrylamide shortened the width of the brain and spinal cord, indicating neuronal toxicity. In summary, acrylamide induces developmental toxicity and neurotoxicity in zebrafish. This can be used to study acrylamide neurotoxicity in a rapid and cost-efficient manner.

Doxycycline Interferes With Tau Aggregation and Reduces Its Neuronal Toxicity

Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts α-synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the 2N4R and K18 isoforms of tau protein in a dose-dependent manner. Furthermore, in a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.

Treating Neurodegenerative Disease with Antioxidants: Efficacy of the Bioactive Phenol Resveratrol and Mitochondrial-Targeted MitoQ and SkQ

Growing evidence from neurodegenerative disease research supports an early pathogenic role for mitochondrial dysfunction in affected neurons that precedes morphological and functional deficits. Resulting oxidative stress and respiratory malfunction contribute to neuronal toxicity and may enhance the vulnerability of neurons to continued assault by aggregation-prone proteins. Consequently, targeting mitochondria with antioxidant therapy may be a non-invasive, inexpensive, and viable means of strengthening neuronal health and slowing disease progression, thereby extending quality of life. We review the pre-clinical and clinical findings available to date of the natural bioactive phenol resveratrol and two synthetic mitochondrial-targeted antioxidants MitoQ and SkQ.

Towards deciphering the Nt17 code: How the sequence and conformation of the first 17 amino acids in Huntingtin regulate the aggregation, cellular properties and neurotoxicity of mutant Httex1

The first 17 N-terminal amino acids (the Nt17 domain) flanking the polyQ tract of the Huntingtin protein (Htt) play an important role in modulating its aggregation, life cycle, membrane binding, and toxicity. Therefore, a better understanding of the molecular and structural determinants of the Nt17 code would likely provide important insights and help guide the development of future anti-aggregation and Htt lowering therapeutic strategies. Towards this goal, we sought to elucidate the role of the Nt17 sequence and helical conformation in regulating mutant Httex1 aggregation, morphology, uptake, and neuronal toxicity. To modulate the helical conformation of Nt17, we used a helix and membrane-binding disrupting mutation (M8P) strategy and site-specific introduction of post-translational modifications that are known to enhance (pT3) or disrupt (pS13, pS16, or pS13/pS16) the overall helicity of Nt17. Our in vitro studies show that the Nt17 and polyQ domains synergistically promote Httex1 aggregation, consistent with previous findings. However, we show that the Nt17 sequence, but not its helical conformation, is a key determinant of the morphology and growth of Httex1 fibrils. In cells, we show that the aggregation propensity and the toxic properties of de novo Httex1 were dependent on both the Nt17 sequence and its helical conformation and the synergistic effect of the Nt17 and polyQ domains. Finally, we demonstrate that the uptake of Httex1 into primary striatal neurons is strongly influenced by the helical propensity of Nt17. Phosphorylation (at T3 or S13/S16) or removal of the Nt17 domain increases the uptake and accumulation of Httex1 fibrils into the nucleus and induces neuronal cell death. Altogether our results demonstrate that the Nt17 domain serves as one of the key master regulators of Htt aggregation and toxicity and represents an attractive target for inhibiting Htt aggregate formation, inclusion formation, cell-to-cell propagation, and neuronal toxicity. These findings have significant implications for targeting the Nt17 domain to develop new disease-modifying therapies for the treatment of Huntington’s disease.