George Perry

Assembly In Vitro of Tau Protein and its Implications in Alzheimers Disease

Tau is a microtubule associated protein that is also the main component of the aberrant filaments that form aberrant structures like the neuropil threads or the neurofibrillary tangles, found in the brain of Alzheimers disease patients. The assembly of tau aberrant filaments could be reproduced in vitro by using a high concentration of tau protein or, at lower protein concentrations, by adding some compounds like polyanions, fatty acids (and derivates), and others. In this mini-review a descriptive analysis of the different conditions needed for in vitro tau polymerization are summarized.

Chapter 20 – Prospects for Antioxidant Therapy in Mild Cognitive Impairment and Alzheimer's Disease

Most of the known genetic, medical, environmental, and lifestyle-related factors for Alzheimers disease (AD) are associated with increased oxidative stress (OS). In agreement with this, human cases at the preclinical stage of AD—such as subjects with mild cognitive impairment (MCI), young adults with Down syndrome, as well as cellular and animal models of AD—provide consistent evidence that oxidative insult is a significant and early event in the pathological cascade of AD. This chapter reviews the involvement of OS in AD and studies that suggest that agents or nutrients inhibiting free-radical formation reduce the incidence of AD. Not only agents or nutrients such as vitamins C and E but also estrogen, nonsteroidal anti-inflammatory drugs, statins, omega-3 polyunsaturated fatty acids, and wine have been proven to have antioxidant activity and, importantly, have all been shown to reduce the incidence of AD. A combination of complex mixtures of antioxidants may be an effective strategy for the treatment of MCI and AD.

Neuroinflammatory Environments Promote Amyloid-ß Deposition and Posttranslational Modification

Indisputable evidence indicates that an inflammatory response is associated with neuron and neurite damage and the deposition of amyloid s (As) and neurofibrillary tangles (NFT) in Alzheimer disease (AD) (see, ref. 1 for a comprehensive review). Just as in the periphery, where degenerating tissue and insoluble materials (resulting from trauma, embolism, and rupture) promote inflammation, these classical stimulants also promote inflammation in the AD brain. From a spatio-temporal perspective, the stimuli promoting neuroinflammation are microlocalized and are present from early preclinical to the terminal stages of AD. Likewise, the upregulation of acute-phase proteins, complement, cytokines, and other inflammatory mediators also is microlocalized and chronic.

Constructing a neuroethical framework for Alzheimers disease research employing big data

C palsy (CP) has significant impact on both patients and society. As there are no curative therapies for CP, stem cells have been proposed as a possible treatment. Human umbilical cord blood cells (HUCBC) containing stem and progenitor cells have been used to treat genetic brain diseases. Previously, HUCBC improved outcomes after hypoxic-ischemic injury in small animals. Clinical trials using HUCBC are underway for neonatal injury and CP. We tested HUCBC therapy in a rabbit model of CP following hypoxic-ischemic (H-I) injury. Following uterine ischemia at 70% gestation, we infused HUCBC in a randomized fashion to newborn rabbit kits after birth with either mild or severe neurobehavioral changes. Infusion of high dose HUCBC, 5x106 cells, dramatically altered the natural history of the injury alleviating the abnormal phenotype including posture, righting reflex, locomotion, tone, and dystonia. Half the high dose showed lesser but still significant improvement. The swimming test however showed that joint function did not restore to naïve control function in either group. Tracing HUCBCs with either MRI biomarkers or PCR for human DNA found little penetration of HUCBC in the newborn brain in the immediate newborn period, suggesting that the beneficial effects were not due to cellular integration or direct proliferative effects but rather to paracrine signaling. In a large animal model, HUCBC improves motor performance in a dose-dependent manner perhaps by improving compensatory repair processes.I social interaction is the most prominent and drug treatment-resistant of core autism symptoms. Clinical findings and rodent studies demonstrate serotonin transmission is often disrupted in the socially-deficient brain. For example, dietary or pharmacological depletion of the 5-HT precursor tryptophan (TRP) worsens behavioral symptoms of autism in patients and impairs social interactions in mice, while TRP supplementation improved sociability in some mouse models of autistic symptoms. Also drugs such as buspirone, pargyline and vortioxetine that mimic some postsynaptic effects of serotonin are able to enhance murine social behavior within a limited dose range or time frame. The selective serotonin reuptake inhibitor (SSRIs) Prozac (fluoxetine) enhances sociability in mice. Unfortunately, however, it only does so for limited subpopulations of patients with autism. This could be because SSRI efficacy is diminished if 5-HT transporter (SERT) function is compromised by common and rare gene polymorphisms. Aside from SERT, auxilliary transporters of 5-HT in the brain include organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT) collectively known as “uptake 2”. Uptake 2 transporters remove serotonin from extracellular fluid with greater capacity but lower affinity than SERT. Our hypothesis is that if uptake 2 is blocked, impaired social behavior may improve in a broader population of individuals with autism than presently benefit from SSRI treatments. This hypothesis was tested in two socially impaired mouse models, the BTBR T+tf/J strain and SERT knockout mice. We found that blockade of uptake 2 transporters by systemically-administered pseudoisocyanine decynium-22 promoted social behavior in these mice.S is the leading cause of severe neurological disability and results in enormous cost measured in health care and lost productivity. To date, no effective treatment has been found for reducing stroke-induced disability. MLC 601 (NeuroAid) as a Traditional Chinese Medicine has been developed to aid post-stroke recovery. This is a double-blind, placebo-controlled clinical trial study on 150 patients with a recent (less than 3 month) ischemic stroke. All patients were given either MLC 601 (100 patients) or placebo (50 patients), 4 capsules 3 times a day, as an add-on to standard medication of post stroke for 3 months. Baseline characteristics for gender, age and elapsed time from stroke onset and risk factors were not significantly different between two groups (p>0.05). There were no difference in Fugl-Meyer Assessment (FMA) score at baseline; 53.69±23.01 in the MLC 601 and 54.96±24.27 in the control group, p=0.755. FMA scores increases significantly in MLC 601 comparing to controls in 4th week (77.13±19.22 vs. 63.50±24.21; p<0.001), 8th week (82.51±14.27 vs. 72.06±21.41; p=0.001) and 12th week (86.22±12.34 vs. 82.78±14.93; p<0.001) after medication. Repeated measured analysis showed statistically difference in FMA during 12 months between two groups (p<0.001). Patients showed a good tolerability to treatment and adverse events were mild and transient. MLC 601 showed better motor recovery than placebo and was safe on top of standard ischemic stroke medication. It was more effective in motor recovery in subjects with severe and moderate than mild patients. However, still more clinical trials are needed to evaluate safety and efficacy of MLC 601 for stroke recovery.A to opioid drugs is a serious clinical and social problem. Withdrawal-induced symptoms are the main cause of keeping drug-dependent individuals craving for continued opioids. Hydrogen sulfide (H2S) is a novel endogenous neuromodulator. The role of H2S in opioid induced syndrome was investigated in the present study. We found that exogenous application of NaHS, an H2S donor, significantly alleviated naloxone-precipitation induced robust withdrawal jumping in mice. Application of NaHS or stimulation of endogenous H2S production suppressed naloxone precipitation induced cAMP rebound and CREB phosphorylation. Our data suggest that H2S may produce beneficial effects against opioid addiction by suppression of AC/cAMP /CREB pathway. Hyperalgesia often occurs in opioid-induced withdrawal syndrome. In the present study, we also studied the effect of H2S on opioid withdrawal induced hyperalgesia. We found that application of NaHS together with three hourly injections of DAMGO (a μ-opioid receptor agonist) attenuated naloxoneprecipitated withdrawal hyperalgesia. RT-PCR and Western blot analysis showed that NaHS significantly reversed the gene and protein expression of up-regulated spinal calcitonin gene-related peptide (CGRP) in naloxone-treated animals. NaHS also inhibited naloxone-induced cAMP rebound and cAMP response element-binding protein (CREB) phosphorylation in rat spinal cord. In addition, NaHS pretreatment suppressed naloxone-stimulated activation of protein kinase C (PKC) α, Raf-1, and extracellular signal-regulated kinase (ERK) 1/2 in rat spinal cord. In conclusion, our data suggest that H2S prevents the development of opioid withdrawal induced symptoms via suppression of synthesis of CGRP through inhibition of AC/cAMP and PKC/Raf-1/ERK pathways.Neurodegenerative disorders usually show characteristic cognitive profiles, determined by the anatomical dispersion of neuronal loss. Short-term/memory decline is a presenting symptom on Alzheimer’ ...A E e4 allele (APOE4) is strongest genetic risk facot for late-onset Alzheimers disease (AD). Brain vascular and metabolic deficits can occur in cognitively normal APOE4 carriers decades before the onset of AD. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of AD-like symptoms in pre-symptomatic APOE4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that APOE4 mice treated with rapamycin had restored cerebral blood flow, blood-brain barrier integrity and glucose metabolism, compared to ageand gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the APOE4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human APOE4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future AD intervention studies in human subjects.W the entorhinal cortex (EC) receives profuse dopaminergic innervations from the midbrain, the effects of dopamine (DA) on GABAergic interneurons in this brain region have not been determined. We probed the actions of DA on GABAA receptor-mediated synaptic transmission in the EC. Application of DA increased the frequencies not the amplitudes of sIPSCs and mIPSCs recorded from entorhinal principal neurons but slightly reduced the amplitude of the evoked IPSCs. The effects of DA were unexpectedly found to be mediated by α1 adrenoreceptors not by DA receptors. DA endogenously released by application of amphetamine also increased sIPSC frequency. Ca2+ influx via T-type Ca2+ channels was required for DA-induced facilitation of sIPSCs and mIPSCs. DA depolarized and enhanced the firing frequency of action potentials of interneurons. DA-induced depolarization was independent of extracellular Na+ and Ca2+ and did not require the functions of Ih channels and T-type Ca2+ channels. DA-generated currents showed a reversal potential close to the K+ reversal potential and inward rectification suggesting that DA inhibits the inward rectifier K+ channels (Kirs). Our results demonstrate that DA facilitates GABA release by activating α1 adrenoreceptors to inhibit Kirs which further depolarize interneurons resulting in secondary Ca2+ influx via T-type Ca2+ channels.

Chronic traumatic encephalopathy: Is a role for biomarkers premature?

I air quality and biomass smoke within indigenous communites is an emerging topic of significant public health concern. Wood stove use is highly prevalent within many reservation communities and biomass smoke associated with cooking and heating has been associated with chronic health problems. Studies conducted in rural and Native American communities examining indoor levels of fine particulate matter (PM2.5) have frequently found levels that exceeded current health-based air quality standards. Native elderly populations are particularly susceptible to reduced lung function or chronic conditions such as asthma, COPD, and bronchitis. Research conducted by our team has demonstrated that improving the efficacy of household level interventions (e.g., air filtration units) can reduce indoor exposures to biomass smoke and therefore lead to improved health outcomes. The findings from these interventions and qualitative input from wood stove experts, suggests that education interventions related to demonstrated best-practices in wood stove operation and fuel efficiency can translate to low-cost and sustainable strategies for reducing indoor biomass combustion exposures. This recently funded project is guided by community-based participatory research principles in order to create more effective and culturally centered intervention methods to improve indoor air quality. The household level intervention is coupled with a community level intervention that was developed and initiated by tribal stakeholders. This presentation will provide information about environmental concerns within indigenous communities and describe the initial work to culturally adapt the approaches and initial intervention planning. The presentation will seek to advance knowledge regarding community-based efforts to increase the translational public health impact of indoor air quality educational materials and interventions.A important requirement of emergent therapeutics will be the development of pharmaceutical technologies suitable for sustained and preventive health care in remote and sub-optimal environmental conditions. Availability of sustained, stable and targeted delivery of pharmaceuticals for preventive health of major organ systems including gastrointestinal, hepatorenal, musculo-skeletal and immune function are essential for effective pharmacotherapeutics. Specifically, pharmaceutical demands may include multi-drug combinations for hormone replacement, radiation protection, immune enhancement and organ function restoration. Additionally, extended stability of pharmaceuticals dispensed must be also considered in future drug development. Emerging technologies that can deliver stable and multi-therapy pharmaceutical preparations and delivery systems include nanotechnology based drug delivery platforms, targeted-delivery systems in non-oral and non-parenteral formulation matrices. Synthetic nanomaterials designed with molecular precision offer defined structures, electronics, and chemistries to be efficient drug carriers with clear advantages over conventional materials of drug delivery matricies. Nanocarrier materials like the bottle brush polymers may be suitable for systemic delivery of drug cocktails while Superparamagnetic Iron Oxide Nanoparticles or (SPIONS) have great potential to serve as carriers for targeted drug delivery to a specific site. These and other emerging concepts of drug delivery and extended shelf-life technologies will be reviewed in light of their application to address health-care challenges of the future. Innovations in alternate treatments for sustained immune enhancement and infection control will be also discussed.In the present study, we did the non -compartmental pharmacokinetics study of amlodipine using high performance liquid chromatography with ultraviolet detector (HPLC-UV) in wistar rats. Rats were allocated to two groups; intravenous group (IV study n=6) and oral group (PO study n=6).In both groups, surgical procedures were carried out under Ketamine HCL (40 mg/kg) and Diazepam (1.5mg/kg) general anesthesia (intramuscular injection).The blood samples were collected at different time interval and were analyzed using HPLC-UV system. Results showed that Amlodipine had a short terminal half-life with relatively high distribution volumes during the steady and terminal phases, and with low plasma clearance. Furthermore, the availability ratio of amlodipine through the intravenous route was higher than that through the oral route, indicating that first pass metabolism and hepatic blood flow are important factor of drug elimination of amlodipine. Bioavailability was estimated to be 78.60 ± 21.33% based on the AUCinf ratios of oral and intravenous administration.R advances in genomics technologies exert profound impact on the biomedical sciences. The main goal of the pharmaceutical sciences is to understand individual differences in drug response and toxicity, as a foundation for developing and guiding therapy for each patient. Bioavailability and bioequivalence represent important factors in the design of optimal drug therapy. Both genetic variants and epigenetic factors, and interplay between them, determine a portion of inter-individual variability, with expression of drug metabolizing enzymes (DMEs) and transporters playing a key role. A number of genetic variants have already been incorporated into pharmacogenetic biomarker tests, but the vast majority of (epi) genetic variability remains hidden. We have implemented gene-by-gene and genome-wide methods to search for pharmacologically relevant variants and regulatory processes, using next generation sequencing of DNA and RNA (RNAseq of coding and non-coding RNAs). A survey of DME and transporter expression reveals distinct expression profiles in various tissues, and the presence of multiple RNA transcripts at each gene locus (such as splice variants). Broad understanding of the regulation of DMEs and transporters has the potential to guide drug development and clinical application.