Perinatal exposure to PFOS and sustained high-fat diet promote neurodevelopmental disorders via genomic reprogramming of pathways associated with neuromotor development.

Perfluorooctanesulfonic acid (PFOS) is a neurotoxic widespread organic contaminant which affects several brain functions including memory, motor coordination and social activity. PFOS has the ability to traverse the placenta and the blood brain barrier (BBB) and cause weight gain in female mice. It's also known that obesity and consumption of a high fat diet have negative effects on the brain, impairs cognition and increases the risk for the development of dementia. The combination effect of developmental exposure to PFOS and the intake of a high-fat diet (HFD) has not been explored. This study investigates the effect of PFOS and /or HFD on weight gain, behavior and transcriptomic and proteomic analysis of adult brain mice. We found that female mice exposed to PFOS alone showed an increase in weight, while HFD expectedly increased body weight. The combination of HFD and PFOS exacerbated generalized behavior such as time spent in the center and rearing, while PFOS alone impacted the distance travelled. These results suggest that PFOS exposure may promote hyperactivity. The combination of PFOS and HFD alter social behavior such as rearing and withdrawal. Although HFD interfered with memory retrieval, biomarkers of dementia did not change except for total Tau and phosphorylated Tau. Tau was impacted by either or both PFOS exposure and HFD. Consistent with behavioral observations, global cerebral transcriptomic analysis showed that PFOS exposure affects calcium signaling, MAPK pathways, ion transmembrane transport, and developmental processes. The combination of HFD with PFOS enhances the effect of PFOS in the brain and affects pathways related to ER stress, axon guidance and extension, and neural migration. Proteomic analysis showed that HFD enhances the impact of PFOS on inflammatory pathways, regulation of cell migration and proliferation, and MAPK signaling pathways. Overall, these data show that PFOS combined with HFD may reprogram the genome and modulate neuromotor development and may promote symptoms linked to attention deficit-hyperactivity disorders (ADHD) and autism spectrum disorders (ASD). Future work will be needed to confirm these connections.

Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer's Disease and Related Disorders.

The field of Alzheimer's disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs that interfere with sequence-specific DNA binding at transcription start sites and predominantly modulate the expression of SP1 target genes. More importantly, the proteome of treated cells displayed ~75% of the downregulated products as SP1 targets. Specific levels of SP1-driven genes and AD biomarkers such as amyloid precursor protein (APP) and Tau proteins were also decreased as part of this targeted systemic response. These small molecules, therefore, offer a viable alternative to achieving desired therapeutic outcomes by interfering with both amyloid and Tau pathways with limited off-target systemic changes.

Pomegranate ellagitannin-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation in vitro.

OBJECTIVES: Urolithins, ellagitannin-gut microbial-derived metabolites, have been reported to mediate pomegranate's neuroprotective effects against Alzheimer's disease (AD), but there are limited data on their effects against neuroinflammation. Herein, we: (1) evaluated whether urolithins (urolithins A and B and their methylated derivatives) attenuate neuroinflammation in murine BV-2 microglia and human SH-SY5Y neurons, and (2) evaluated hippocampus of transgenic AD (R1.40) mice administered a pomegranate extract (PE; 100 or 200 mg/kg/day for 3 weeks) for inflammatory biomarkers. METHODS: Effects of urolithins (10 µM) on inflammatory biomarkers were evaluated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. In a non-contact co-culture cell model, SH-SY5Y cell viability was assessed after exposure to media collected from LPS-BV-2 cells treated with or without urolithins. Effects of urolithins on apoptosis and caspase 3/7 and 9 release from H2O2-induced oxidative stress of BV-2 and SH-SY5Y cells were assessed. Hippocampal tissues of vehicle and PE-treated transgenic R1.40 mice were evaluated for gene expression of inflammatory biomarkers by qRT-PCR. RESULTS: Urolithins decreased media levels of nitric oxide, interleukin 6 (IL-6), prostaglandin E2, and tumor necrosis factor alpha from LPS-BV-2 microglia. In the co-culture cell model, media from LPS-BV-2 cells treated with urolithins preserved SH-SY5Y cell viability greater than media from cells treated without urolithins. Urolithins mitigated apoptosis and caspase 3/7 and 9 release from H2O2-induced oxidative stress of BV-2 and SH-SY5Y cells. While not statistically significant, inflammatory biomarkers (TNF-α, COX-2, IL-1, and IL-6) appeared to follow a decreasing trend in the hippocampus of high-dose PE-treated animals compared to controls. DISCUSSION: The attenuation of neuroinflammation by urolithins may contribute, in part, toward pomegranate's neuroprotective effects against AD.

Tolfenamic acid reduces tau and CDK5 levels: implications for dementia and tauopathies.

Tau and its aggregates are linked to the pathology of Alzheimer's disease (AD) and other tauopathies and, therefore, are explored as therapeutic targets for such disorders. Tau belongs to a family of microtubule-associated proteins that promote microtubule assembly. When hyperphosphorylated, tau becomes prone to forming aggregates. Increased brain levels of hyperphosphorylated tau correlate with dementia. Specificity protein 1 (Sp1), a transcription factor elevated in AD, is responsible for the transcription of AD-related proteins including the amyloid precursor protein, tau, and its cyclin-dependent kinase-5 (CDK5) activators. Tolfenamic acid promotes the degradation of Sp1, our previous studies demonstrated its ability to down-regulate transcriptional targets of Sp1 like amyloid precursor protein and reduce amyloid beta (Aß), the main component of AD plaques. In this study, we administered tolfenamic acid daily to hemizygous R1.40 transgenic mice for 34 days, and examined tau and CDK5 gene and protein expression within the brain. Our results demonstrate that tolfenamic acid lowers tau mRNA and protein, as well as the levels of its phosphorylated form and CDK5. Thus, we present a drug candidate that inhibits the transcription of multiple major intermediates in AD pathology, thereby helping uncover a new mechanism-based approach for targeting AD. A new approach for targeting Alzheimer's disease through a transcriptional based mechanism is presented. Tolfenamic acid lowers the levels of tau, which forms pathological aggregates in Alzheimer's disease and other tauopathies, by promoting the degradation of the transcription factor specificity protein 1 which regulates tau transcription.

Infantile exposure to lead and late-age cognitive decline: relevance to AD.

BACKGROUND: Early-life lead (Pb) exposure induces overexpression of the amyloid beta precursor protein and its amyloid beta product in older rats and primates. We exposed rodents to Pb during different life span periods and examined cognitive function in old age and its impact on biomarkers associated with Alzheimer's disease (AD). METHODS: Morris, Y, and the elevated plus mazes were used. Western blot, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay were used to study the levels of AD biomarkers. RESULTS: Cognitive impairment was observed in mice exposed as infants but not as adults. Overexpression of AD-related genes (amyloid beta precursor protein and ß-site amyloid precursor protein cleaving enzyme 1) and their products, as well as their transcriptional regulator-specificity protein 1 (Sp1)-occurred only in older mice with developmental exposure to Pb. CONCLUSIONS: A window of vulnerability to Pb neurotoxicity exists in the developing brain that can influence AD pathogenesis and cognitive decline in old age.

Pharmacotherapies for the Treatment of Progressive Supranuclear Palsy: A Narrative Review.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder resulting from the deposition of misfolded and neurotoxic forms of tau protein in specific areas of the midbrain, basal ganglia, and cortex. It is one of the most representative forms of tauopathy. PSP presents in several different phenotypic variations and is often accompanied by the development of concurrent neurodegenerative disorders. PSP is universally fatal, and effective disease-modifying therapies for PSP have not yet been identified. Several tau-targeting treatment modalities, including vaccines, monoclonal antibodies, and microtubule-stabilizing agents, have been investigated and have had no efficacy. The need to treat PSP and other tauopathies is critical, and many clinical trials investigating tau-targeted treatments are underway. In this review, the PubMed database was queried to collect information about preclinical and clinical research on PSP treatment. Additionally, the US National Library of Medicine's ClinicalTrials.gov website was queried to identify past and ongoing clinical trials relevant to PSP treatment. This narrative review summarizes our findings regarding these reports, which include potential disease-modifying drug trials, modifiable risk factor management, and symptom treatments.

Cellular and organismal toxicity of the anti-cancer small molecule, tolfenamic acid: a pre-clinical evaluation.

BACKGROUND/AIMS: The small molecule, Tolfenamic acid (TA) has shown anti-cancer activity in pre-clinical models and is currently in Phase I clinical trials at MD Anderson Cancer Center Orlando. Since specificity and toxicity are major concerns for investigational agents, we tested the effect of TA on specific targets, and assessed the cellular and organismal toxicity representing pre-clinical studies in cancer. METHODS: Panc1, L3.6pl, and MiaPaCa-2 (pancreatic cancer), hTERT-HPNE(normal), and differentiated/un-differentiated SH-SY5Y (neuroblastoma) cells were treated with increasing concentrations of TA. Cell viability and effect on specific molecular targets, Sp1 and survivin were determined. Athymic nude mice were treated with vehicle or TA (50mg/kg, 3times/week for 6 weeks) and alterations in the growth pattern, hematocrit, and histopathology of gut, liver, and stomach were monitored. RESULTS: TA treatment decreased cell proliferation and inhibited the expression of Sp1 and survivin in cancer cells while only subtle response was observed in normal (hTERT-HPNE) and differentiated SH-SY5Y cells. Mice studies revealed no effect on body weight and hematocrit. Furthermore, TA regimen did not cause signs of internal-bleeding or damage to vital tissues in mice. CONCLUSION: These results demonstrate that TA selectively inhibits malignant cell growth acting on specific targets and its chronic treatment did not cause apparent toxicity in nude mice.

Fenamates as Potential Therapeutics for Neurodegenerative Disorders.

Neurodegenerative disorders are desperately lacking treatment options. It is imperative that drug repurposing be considered in the fight against neurodegenerative diseases. Fenamates have been studied for efficacy in treating several neurodegenerative diseases. The purpose of this review is to comprehensively present the past and current research on fenamates in the context of neurodegenerative diseases with a special emphasis on tolfenamic acid and Alzheimer's disease. Furthermore, this review discusses the major molecular pathways modulated by fenamates.

Developmental Perfluorooctanesulfonic acid (PFOS) exposure as a potential risk factor for late-onset Alzheimer's disease in CD-1 mice and SH-SY5Y cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for approximately 60-80% of dementia cases worldwide and is characterized by an accumulation of extracellular senile plaques composed of ß-amyloid (Aß) peptide and intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau protein. Sporadic or late-onset AD (LOAD) represents 95 % of the AD cases and its etiology does not appear to follow Mendelian laws of inheritance, thus, implicating the role of epigenetic programming and environmental factors. Apolipoprotein allele 4 (ApoE4), the only established genetic risk factor for LOAD, is suggested to accelerate the pathogenesis of AD by increasing tau hyperphosphorylation, inhibiting the clearance of amyloid-ß (Aß), and promoting Aß aggregation. Perfluorooctanesulfonic acid (PFOS) is a persistent organic pollutant, with potential neurotoxic effects, that poses a major threat to the ecosystem and human health. By employing in vivo and in vitro models, the present study investigated PFOS as a potential risk factor for LOAD by assessing its impact on amyloidogenesis, tau pathology, and rodent behavior. Our behavioral analysis revealed that developmentally exposed male and female mice exhibited a strong trend of increased rearing and significantly increased distance traveled in the open field test. Biochemically, GSK3ß and total ApoE were increased following developmental exposure, in vivo. Furthermore, in vitro, low concentrations of PFOS elevated protein levels of APP, tau, and its site-specific phosphorylation. Differentiated SH-SY5Y cells exposed to a series of PFOS concentrations, also, had elevated protein expression of GSK3ß. These data suggest that total ApoE is inducible by environmental exposure to PFOS.

Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD.

The sporadic nature of Alzheimer's disease (AD) argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead (Pb) during brain development predetermined the expression and regulation of the amyloid precursor protein (APP) and its amyloidogenic beta-amyloid (Abeta) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (beta-site APP cleaving enzyme 1)] as well as their transcriptional regulator (Sp1) were elevated in aged (23-year-old) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD.

Co-localization and distribution of cerebral APP and SP1 and its relationship to amyloidogenesis.

Alzheimer's disease is characterized by amyloid-beta peptide (Abeta)-loaded plaques in the brain. Abeta is a cleavage fragment of amyloid-beta protein precursor (APP) and over production of APP may lead to amyloidogenesis. The regulatory region of the APP gene contains consensus sites recognized by the transcription factor, specificity protein 1 (SP1), which has been shown to be required for the regulation of APP and Abeta. To understand the role of SP1 in APP biogenesis, herein we have characterized the relative distribution and localization of SP1, APP, and Abeta in various brain regions of rodent and primate models using immunohistochemistry. We observed that overall distribution and cellular localization of SP1, APP, and Abeta are similar and neuronal in origin. Their distribution is abundant in various layers of neocortex, but restricted to the Purkinje cell layer of the cerebellum, and the pyramidal cell layer of hippocampus. These findings suggest that overproduction of Abeta in vivo may be associated with transcriptional pathways involving SP1 and the APP gene.

The environment, epigenetics and amyloidogenesis.

Alzheimer's Disease (AD) is a progressive, irreversible neurodegenerative disease. Despite several genetic mutations (Haass et al., J. Biol. Chem. 269:17741-17748, 1994; Ancolio et al., Proc. Natl. Acad. Sci. USA 96:4119-4124, 1999; Munoz and Feldman, CMAJ 162:65-72, 2000; Gatz et al., Neurobiol. Aging 26:439-447, 2005) found in AD patients, more than 90% of AD cases are sporadic (Bertram and Tanzi, Hum. Mol. Genet. 13:R135-R141, 2004). Therefore, it is plausible that environmental exposure may be an etiologic factor in the pathogenesis of AD. The AD brain is characterized by extracellular beta-amyloid (Abeta) deposition and intracellular hyperphosphorylated tau protein. Our lab has demonstrated that developmental exposure of rodents to the heavy metal lead (Pb) increases APP (amyloid precursor protein) and Abeta production later in the aging brain (Basha et al., J. Neurosci. 25:823-829, 2005a). We also found elevations in the oxidative marker 8-oxo-dG in older animals that had been developmentally exposed to Pb (Bolin et al., FASEB J. 20:788-790, 2006) as well as promotion of amyloidogenic histopathology in primates. These findings indicate that early life experiences contribute to amyloidogenesis in old age perhaps through epigenetic pathways. Here we explore the role of epigenetics as the underlying mechanism that mediates this early exposure-latent pathogenesis with a special emphasis on alterations in the methylation profiles of CpG dinucleotides in the promoters of genes and their influence on both gene transcription and oxidative DNA damage.

Gene expression profiles in the cerebellum and hippocampus following exposure to a neurotoxicant, Aroclor 1254: developmental effects.

The developmental consequences of exposure to the polychlorinated biphenyls (PCBs) have been widely studied, making PCBs a unique model to understand issues related to environmental mixture of persistent chemicals. PCB exposure in humans adversely affects neurocognitive development, causes psychomotor difficulties, and contributes to attention deficits in children, all of which seem to be associated with altered patterns of neuronal connectivity. In the present study, we examined gene expression profiles in the rat nervous system following PCB developmental exposure. Pregnant rats (Long-Evans) were dosed perinatally with 0 or 6 mg/kg/day of Aroclor 1254 from gestation day 6 through postnatal day (PND) 21. Gene expression in cerebellum and hippocampus from PND7 and PND14 animals was analyzed with an emphasis on developmental aspects. Changes in gene expression (> or =1.5 fold) in control animals identified normal developmental changes. These basal levels of expression were compared to data from Aroclor 1254-treated animals to determine the impact of gestational PCB exposure on developmental parameters. The results indicate that the expression of a number of developmental genes related to cell cycle, synaptic function, cell maintenance, and neurogenesis is significantly altered from PND7 to PND14. Aroclor 1254 treatment appears to dampen the overall growth-related gene expression levels in both regions with the effect being more pronounced in the cerebellum. Functional analysis suggests that Aroclor 1254 delays maturation of the developing nervous system, with the consequences dependent on the ontological state of the brain area and the functional role of the individual gene. Such changes may underlie learning and memory deficits observed in PCB exposed animals and humans.

An initial animal proof-of-concept study for central administration of clozapine to schizophrenia patients.

While clozapine is the acknowledged superior pharmacotherapeutic for the treatment of schizophrenia, the side effect profile, which includes potentially fatal complications, limits its usefulness. Central administration of clozapine directly into the brain could circumvent many of the side effect issues due to the dramatic reduction in dose and the limitation of the drug primarily to the CNS. The present study demonstrates that clozapine can be formulated as a stable solution at physiological pH, which does not have in vitro neurotoxic effects at concentrations which may be effective at treating symptoms. Acute central administration improved auditory gating deficits in a mouse model of schizophrenia-like deficits. Assessment of behavioral alterations in rats receiving chronic central infusions of clozapine via osmotic minipump was performed with the open field and elevated plus mazes. Neither paradigm revealed any detrimental effects of the infusion. While these data represent only an initial investigation, they none-the-less suggest that central administration of clozapine may be a viable alternate therapeutic approach for schizophrenia patients which may be effective in symptom reduction without causing behavioral or neurotoxic effects.

Latent consequences of early-life lead (Pb) exposure and the future: Addressing the Pb crisis.

BACKGROUND: The lead (Pb) exposure crisis in Flint, Michigan has passed from well-publicized event to a footnote, while its biological and social impact will linger for lifetimes. Interest in the "water crisis" has dropped to pre-event levels, which is neither appropriate nor safe. Flint's exposure was severe, but it was not unique. Problematic Pb levels have also been found in schools and daycares in 42 states in the USA. The enormity of Pb exposure via municipal water systems requires multiple responses. Herein, we focus on addressing a possible answer to long-term sequelae of Pb exposure. We propose "4R's" (remediation, renovation, reallocation, and research) against the Pb crisis that goes beyond a short-term fix. Remediation for affected individuals must continue to provide clean water and deal with both short and long-term effects of Pb exposure. Renovation of current water delivery systems, at both system-wide and individual site levels, is necessary. Reallocation of resources is needed to ensure these two responses occur and to get communities ready for potential sequelae of Pb exposure. Finally, properly focused research can track exposed individuals and illuminate latent (presumably epigenetic) results of Pb exposure and inform further resource reallocation. CONCLUSION: Motivation to act by not only the general public but also by scientific and medical leaders must be maintained beyond initial news cycle spikes and an annual follow-up story. Environmental impact of Pb contamination of drinking water goes beyond one exposure incident in an impoverished and forgotten Michigan city. Population effects must be addressed long-term and nationwide.

Influence of Early Life Lead (Pb) Exposure on α-Synuclein, GSK-3ß and Caspase-3 Mediated Tauopathy: Implications on Alzheimer's Disease.

BACKGROUND: Previously we have shown that developmental exposure to the heavy metal lead (Pb) resulted in latent cognitive impairment, upregulation of biomarkers and pathology associated with both the tau and amyloid pathways, however, the impact on Alpha Synuclein (α-Syn) and its relationship to these pathways and their connection to cognitive performance warrant further elucidation. OBJECTIVE: The present study determined the impact of developmental Pb exposure on the α-Syn pathways in a mouse model knock-out (KO) for murine tau gene and in differentiated human neuroblastoma SHSY5Y cell line exposed to a series of Pb concentrations. METHODS: Western blot analysis and RT-PCR were used to assess the levels of intermediates in the tau and α-Syn pathways following postnatal Pb exposure on aged mice lacking tau gene and in differentiated SHSY5Y cells on day 3 and day 6 after the Pb exposure had ceased. RESULT: Early life Pb exposure is accompanied by latent up-regulation in α-Syn in these mice. Furthermore, prior exposure to Pb in-vitro also resulted in an increase in α-Syn, its phosphorylated forms, as well as an increase in glycogen synthase kinase 3ß (GSK-3ß) and Caspase-3. CONCLUSION: An environmental agent can act as a latent inducer of both α-Syn and associated kinases that are involved in tau hyperphosphorylation and may allude to the interactive nature of these two neurodegenerative pathways.

Altered microRNA, mRNA, and Protein Expression of Neurodegeneration-Related Biomarkers and Their Transcriptional and Epigenetic Modifiers in a Human Tau Transgenic Mouse Model in Response to Developmental Lead Exposure.

Amyloid deposits originating from the amyloid-ß protein precursor (AßPP) and aggregates of the microtubule associated protein tau (MAPT) are the hallmarks of Alzheimer's disease (AD). Animal studies have demonstrated a link between early life exposure to lead (Pb) and latent overexpression of the AßPP and MAPT genes and their products via epigenetic reprogramming. The present study monitored APP gene and epigenetic mediators and transcription factors known to regulate it. Western blot analysis and quantitative polymerase chain reaction (qPCR) were used to study the mRNA, miRNA, and proteins levels of AßPP, specificity protein 1 (SP1; a transcriptional regulator of amyloid and tau pathway), and epigenetic intermediates namely: DNA methyltransferase (DNMT) 1, DNMT3a and Methyl- CpG protein binding 2 (MeCP2) in the cerebral cortex of transgenic mice (Knock-in for human MAPT). These transgenic mice were developmentally exposed to Pb and the impact on mRNA, miRNA, and protein levels was scrutinized on postnatal days (PND) 20 and 50. The data revealed a consistent inverse relationship between miRNA and protein levels for SP1 and AßPP both in the basal and exposed conditions, which may influence the levels of their corresponding proteins. On the other hand, the relationship between miRNA and protein levels was not correlative for DNMT1 and DNMT3a. MeCP2 miRNA protein levels corresponded only following environmental exposure. These results suggest that developmental exposure to Pb and subsequent AßPP protein levels may be controlled through transcriptional regulators and epigenetic mechanisms that mainly involve miRNA regulation.

Histone acetylation maps in aged mice developmentally exposed to lead: epigenetic drift and Alzheimer-related genes.

AIM: Early life exposure to lead (Pb) has been shown to increase late life biomarkers involved in Alzheimer's disease (AD) pathology. Here, we tested the hypothesis that latent over expression of AD-related genes may be regulated through histone activation pathways. METHODS: Chromatin immunoprecipitation sequencing was used to map the histone activation mark (H3K9Ac) to the mouse genome in developmentally Pb exposed mice on postnatal days 20, 270 and 700. RESULTS: Exposure to Pb resulted in a global downregulation of H3K9Ac across the lifespan; except in genes associated with the Alzheimer pathway. DISCUSSION: Early life exposure to Pb results in an epigenetic drift in H3K9Ac consistent with latent global gene repression. Alzheimer-related genes do not follow this trend.

Tolfenamic Acid: A Modifier of the Tau Protein and its Role in Cognition and Tauopathy.

BACKGROUND: Tangles are deposits of hyperphosphorylated tau, which are found in multiple neurodegenerative disorders that are referred to as tauopathies, of which Alzheimer's disease (AD) is the most common. Tauopathies are clinically characterized by dementia and share common cortical lesions composed of aggregates of the protein tau. OBJECTIVE: In this study, we explored the therapeutic potential of tolfenamic acid (TA), in modifying disease processes in a transgenic animal model that carries the human tau gene (hTau). METHODS: Behavioral tests, Western blotting and Immunohistochemical analysis were used to demonstrate the efficacy of TA. RESULTS: Treatment of TA improved improving spatial learning deficits and memory impairments in young and aged hTau mice. Western blot analysis of the hTau protein revealed reductions in total tau as well as in sitespecific hyperphosphorylation of tau in response to TA administration. Immunohistochemical analysis for phosphorylated tau protein revealed reduced staining in the frontal cortex, hippocampus, and striatum in animals treated with TA. CONCLUSION: TA holds the potential as a disease-modifying agent for the treatment of tauopathies including AD.

Exposure to lead and the developmental origin of oxidative DNA damage in the aging brain.

Oxidative damage to DNA has been associated with neurodegenerative diseases. Developmental exposure to lead (Pb) has been shown to elevate the Alzheimer's disease (AD) related beta-amyloid peptide (Abeta), which is known to generate reactive oxygen species in the aging brain. This study measures the lifetime cerebral 8-hydroxy-2'-deoxyguanosine (oxo8dG) levels and the activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase (Ogg1) in rats developmentally exposed to Pb. Oxo8dG was transiently modulated early in life (Postnatal day 5), but was later elevated 20 months after exposure to Pb had ceased, while Ogg1 activity was not altered. Furthermore, an age-dependent loss in the inverse correlation between Ogg1 activity and oxo8dG accumulation was observed. The effect of Pb on oxo8dG levels did not occur if animals were exposed to Pb in old age. These increases in DNA damage occurred in the absence of any Pb-induced changes in copper/zinc-superoxide dismutase (SOD1), manganese-SOD (SOD2), and reduced-form glutathion (GSH). These data suggest that oxidative damage and neurodegeneration in the aging brain could be impacted by the developmental disturbances.