Aging / Alzheimer's Disease

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    Determining the Viability of Biomarkers for Oxidative Stress Detection in Clinically Afflicted Cohorts
    (2015-03) Duong, Phong; Contreras, Jo G.; Snyder, Brina; O'Bryant, Sid; Cunningham, Rebecca
    Intro: In the US, there are more than 5 million Americans living with Alzheimer’s disease (AD) and approximately 500,000 more are suffering from Parkinson’s disease (PD). Oxidative stress (OS) and its deregulation of reactive oxygen species (ROS) have been implicated as a component of neurodegenerative diseases. Accumulation of ROS is accountable for increasing mitochondrial dysfunction that leads to neuronal apoptosis. In addition to ROS accumulation, OS can result in a number of cellular by-products such as Malondialdehyde (MDA), 8-Isoprostane, and Advanced Oxidation Protein Products (AOPP). Recent studies also suggest that high levels of testosterone can depress cellular resistance to oxidative stress. Purpose: The objective of this research is to determine the viability of laboratory assays as a detection tool for the evaluation of neurodegenerative diseases in aging males. Methods: 352 clinical plasma samples from the Texas Alzheimer’s Research and Care Consortium were used in assay evaluation. The samples were collected from either Caucasian or Hispanic males and evaluated based on 6 previously determined disease statuses. The AOPP Assay was used to detect chlorinated oxidation of plasma proteins. For AOPP, plasma samples were performed with a 1:7 dilution factor. Following preparation, the samples were then plated in duplicates and read at an absorbance of 340nm. To correlate with a previous testosterone study, a Testosterone ELISA was conducted with the use of Rabbit Anti-Free T-Antibody without sample dilution. Once plated, the samples were incubated for 60 minutes, washed, and read at an absorbance of 450nm. MDA can be accounted for in OS-resultant lipid peroxidation (LP). MDA levels in the clinical samples were examined using a Colorimetric TBARS Assay. The assay subjected the samples to boiling, centrifuging, and incubation in an ice bath. The supernatant was then removed, plated, and read at an absorbance of 532nm. Results: The absorbance reading from the AOPP assay and Colorimetric TBARS assay, yielded similar results across all six-disease statuses. Despite the differences in disease status, samples were determined to have triple the amount of MDA concentration compared the control. Conclusion: The similarity in values and discrepancy from the control indicates that AOPP and TBARS cannot accurately determine OS in banked plasma samples. T-ELISA is currently undergoing further scrutiny with the use of mass spectrometry.
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    Worry in Mexican American Elders: The Role of Age, Gender, and Metabolic Syndrome
    (2015-03) Chaphekar, Anita V.; Hall, James; Johnson, Leigh; O'Bryant, Sid
    1. Purpose: Metabolic syndrome (MetS) is defined as risk factors which increase an individual’s risk for cardiovascular disease and diabetes. Risk factors include: abdominal obesity, hypertension, dyslipidemia, and elevated blood glucose. Research has suggested that worry, independent of anxiety, can contribute to poor health effects such as those seen with MetS. Mexican Americans (MA) have a high prevalence of worry and MetS, however a relationship between these variables has yet to be investigated for this population. The purpose of this study was to analyze the relationship between MetS and worry in the MA population. It is hypothesized that individuals with high levels of worry will be more likely to have MetS and show elevated risk factors. This study also examines the effect of age and gender on levels of worry in this population. 2. Methods: This cross-sectional study used data collected from the Health and Aging Brain Study among Latino Elders. Participants were grouped into a high or low worry category based on their Penn State Worry Questionnaire (PSWQ) score. Odds ratio was calculated for the presence of MetS. Independent sample t-tests were used to analyze the following: differences in MetS risk factors between individuals with high and low levels of worry, and differences in levels of worry based on gender and age. 3. Results: Odds ratio calculation was not significant for the presence of MetS (95% CI 0.443-1.163, p = 0.18) between individuals of differing levels of worry. Participants with high and low worry showed a significant difference in abdominal circumference (p = 0.025) and blood glucose (p = 0.038). Males and females showed a significant difference in total PSWQ score (p = 0.000). There was a significant difference in total PSWQ score between individuals aged 61 and above and those aged 60 and below (p = 0.006). 4. Conclusion: Individuals with a high level of worry did not have an increased likelihood to have MetS compared to individuals in a low worry group. However, when analyzing each risk factor alone, participants in a high worry group had a greater abdominal circumference and higher fasting glucose levels compared to those in a low worry group. The results of this study suggest the association of waist size and blood glucose with elevated levels of worry in the MA population. Results showed that females and individuals under the age of 61 have higher levels of worry compared to males and those over the age of 61, respectively.
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    Two dimensional blue native/SDS-PAGE to identify mitochondrial complex I subunits modified by 4-hydroxynonenal (HNE)
    (2015-03) Wu, Jinzi; Luo, Xiaoting; Yan, Liang-Jun
    Abstract The lipid peroxidation product 4-hydroxynonenal (HNE) can form protein-linked HNE adducts, thereby impacting protein structure and function. Mitochondrial complex I (NADH-ubiquinone oxidoreductase), containing at least 45 subunits in mammalian cells, sits in a lipid-rich environment and is thus very susceptible to HNE modifications. In this paper, a procedure for the identification of HNE-modified complex I subunits is described. Complex I was isolated by first dimensional nongradient blue native polyacrylamide gel electrophoresis (BN-PAGE). The isolated complex I band, visualized by either Coomassie blue staining or silver staining, was further analyzed by second dimensional SDS-PAGE. HNE-modified proteins were visualized by Western blotting probed with anti-HNE antibodies. HNE-positive bands were then excised and the proteins contained in them were identified by mass spectrometric peptide sequencing. The method was successfully applied for the identification of two complex I subunits that showed enhanced HNE-modifications in diabetic kidney mitochondria. Keywords: blue native/SDS-PAGE, diabetes, 4-hydroxynonenal, mitochondria, reactive oxygen species, streptozotocin
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    HDL and Cognitive Function in Older Adults: A Systematic Review
    (2015-03) Tshuma, Lisa; Miller, Kagen; Bonham, Karen; Hartos, Jessica
    PURPOSE: The objective of this systematic review was to address the question, “Is High Density Lipoprotein-cholesterol (HDL-C or HDL) related to cognitive function in older adults?” MATERIALS AND METHODS: This systematic review included 17 primary research articles: 8 cross-sectional studies and 9 prospective studies that assess the relationship between HDL and cognitive function in older adults. The search for articles was conducted in July 2014 using online library resources at the UNT Health Science Center. The criteria for selection included (1) primary research articles that reported (2) a measure for HDL-C and (3) at least one measure for cognitive function (4) in older adults. Data was extracted using an individual article review form that assessed the research level, quality, and results for each article. Determination of the evidence base rating was based on the results across articles. RESULTS: The evidence base for the 8 cross-sectional studies did not support a relationship between HDL and cognitive function. However, these articles also did not address a change in cognitive function over time. The evidence from 9 prospective studies did support a relationship between HDL and cognitive function. Six of 9 studies reported baseline HDL levels significantly related to cognitive function. Five studies of 9 demonstrated a relationship between memory and HDL, and controlled for other influential factors, over a time range of 4-7 years. Another study demonstrated a relationship between HDL and language/sensory/motor functions at 16 years. The 4 studies that did not find significant relations had follow-up time periods of 3 years (2 studies), 12 years and 16 years, indicating that relations may be most evident within a limited window of time, and may vary by domain of cognitive function. CONCLUSIONS: The evidence base for prospective studies indicates a significant relationship between HDL and cognitive function. The results also suggest that some cognitive measures may not be equally informative across populations and/or languages. Future research studies should be a minimum of 4-years and extend beyond 16 years, with uniform sampling intervals. Additionally, future studies should control for domains of cognitive function, known factors that influence HDL-C, employ consistent sample and data collection processes, and include diverse populations.
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    Pyruvate induction of Nrf2/ARE-regulated Glyoxalase1 and Glutathione Reductase in porcine brain post-cardiac arrest: enhanced methylglyoxal detoxification
    (2015-03) Scott, Gary F.; Cherry, Brandon H.; Nguyen, A Q.; Hollrah, Roger A.; Williams, Arthur G. Jr.; Mallet, Robert T.
    Abstract Pyruvate induction of Nrf2/ARE-regulated Glyoxalase1 and Glutathione Reductase in porcine brain post-cardiac arrest:enhanced methylglyoxal detoxification.Background:After cardiac arrest (CA) and cardio-cerebral resuscitation (CCR), enhanced glycolysis elevates toxic carbonyl methylglyoxal (MG) that contributes to reactive oxidative/nitrosative stress (RONS), enzyme inactivation and death of neurons and astroglia. Post cardiac arrest cognitive deficits may be prevented by pyruvate infusions that boost glyoxalase 1 (GLO1) detoxification of MG and glutathione (GSH) synthesis by glutathione reductase (GR) via Nrf2/ARE (antioxidant response element)-regulated Phase II gene expression.Hypothesis:Pyruvate-induced cytoprotective mechanisms can curtail brain injury and cognitive deficit after cardiac arrest and resuscitation in pigs.Methods:Compared to sham non-arrest animals, pigs were subjected to CA/CCR, infused with either 4 mM pyruvate or NaCl for one hour, recovered 4 hours prior to sacrifice. Post-mortem frontal cortical lysates were assayed for Nrf2/ARE binding activity, GLO1, GR, and GAPDH (rate-limiting for MG production) activity, while plasma glutamate concentrations were measured.Results:Compared with saline controls, pyruvate infused pigs demonstrated increased Nrf2/ARE binding activity (Fig 1) and 3-fold higher GLO1 activity (Fig 2) supporting MG detoxification, while GR (Fig 3) and GAPDH (Fig 4) were similarly stimulated. Plasma glutamate concentrations were reduced by pyruvate (Fig 5), which would support greater brain clearance of excitotoxic glutamate, according to the brain-to-blood glutamate efflux hypothesis.Conclusions:Intravenous pyruvate induces Nrf2-regulated gene activation for augmented GR, and GLO1 biological activity via mechanisms that may lower glutamate-inflicted excitotoxicity and heretofore untreatable cognitive deficits of post-CA/CCR brain injury.Thus pyruvate infusion may also provide therapeutic benefit for several neurodegenerative disorders of similar etiology.
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    Relationship between Depressive Symptoms and Cognitive Decline
    (2015-03) Ford, Michael A.; Barber, Robert C.; Hall, James
    Objectives: Depression and cognitive decline have a complex relationship. The purpose of our study was to determine if depression, or specific symptoms of depression, influences the rate of cognitive decline. Methods: We conducted linear regression analysis to determine if baseline depression or depressive symptoms influenced the rate of age-related cognitive decline. Data analyzed were from 634 male and 934 female elderly white, non-Hispanic participants in the Texas Alzheimer’s Research and Care Consortium. Participants included cognitively normal controls (733), subjects with mild cognitive impairment (243) and subjects with Alzheimer’s disease (592). Baseline depression was estimated using Geriatric Depression Scale (GDS30) scores. Baseline depressive symptoms included apathy and agitation, as measured in the Neuropsychiatric Inventory Questionnaire (NPI-Q). Cognitive decline was measured by a change in Clinical Dementia Rating (CDR) scores between visits 1 and 3. In these analyses we stratified based on gender and adjusted for age at first visit and education. Results: We found that baseline overall depression (GDS30) was not significantly related to cognitive decline. Specific depressive symptoms were significantly related to cognitive decline, but there were different effects in men and women. Apathy was correlated with increased cognitive decline in men only (p Conclusions: Depressive symptoms appear to increase the rate of cognitive decline and may be early signs for neurodegeneration. These symptoms may also be important targets for therapeutics designed to treat, or slow the progression of Alzheimer’s disease. However, the relationship is not simple, as indicated by the divergent results observed in males and females. Further research in this area is warranted; while there are currently no proven treatments for Alzheimer’s disease, depression and depressive symptoms are therapeutically modifiable.
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    Caloric Restriction and Dietary Curcumin Improve Functional Outcomes of Aging in Mice
    (2015-03) Sarker, Marjana R.; Forster, Michael
    Curcumin, from Curcuma Longa, has antioxidant and anti-inflammatory effects that are hypothesized to benefit impaired functional capacity related to normal aging. The following results are from an ongoing study of dietary curcumin alone and in combination with caloric restriction, testing functional and biochemical outcomes in late middle age (MAG) (15 months) and senescent (AG) (20 months) C57BL/6J male and female mice. Mice were assigned in treatment groups to receive: (i) base diet ad libitum (AL), (ii) weight stable caloric restriction (CR), (iii) curcumin in the base diet (7200 mg/kg diet) (CURAL) or (iv) curcumin plus CR (CURCR). At 8 weeks of treatment, all mice were tested for spatial memory and cognitive flexibility. Cognitive flexibility, tested using a serial reversal task, was significantly better for MAG males under CR and CURAL compared to AL but not under CURCR, suggesting an antagonistic interaction. On the other hand, MAG and AG female experimental groups did significantly better than AL. No interaction of CR and CUR was observed in AG males, with CURAL and CR yielding comparable benefits. None of the treatments had a significant effect on hippocampus- dependent spatial memory performance in MAG or AG. These results suggest that when implemented separately, both CR and CUR treatments have an ameliorative effect on impaired frontal cortical function present in late middle age and senescence. These effects were similar across different behavioral tasks and were non-interactive or antagonistic, suggesting that they could involve the same or similar mechanisms. Therefore, curcumin intake may mimic the effect of CR in the absence of diminished energy intake and weight loss.
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    p38 acts as an activator of presenilin 1 in the brain of alcoholic rats.
    (2015-03) Metzger, Daniel; Jung, Marianna; Das, Hriday
    Purpose: Presenilin 1 (PS1) is originally known as a major protein of which mutation is responsible for age-associated brain disorders such as Alzheimer disease. In addition to this property, interaction between PS1 and other proteins has been reported to mediate various brain damages. Our previous studies have demonstrated that repeated exposure to and withdrawal from a high dose of ethanol provoke the over expression of a stress-activated protein kinase p38 in the rat brains. Here, we investigated whether p38 is an upstream activator of PS1 in a manner that impedes cerebellar-related motoric performance. We also investigated whether p38-PS1 link mediates an excitotoxic stress induced by repeated ethanol exposure and withdrawal. Methods: We employed transgenic mice (p38-KO) lacking p38 in cerebellar neurons and tested motoric performance using Rotarod where a shorter time to fall from rotating apparatus indicates poorer cerebellar function. After Rotarod test, mice were subjected to measure PS1 protein and mRNA level in cerebellum using immunoblot and q-PCR. Separately, young adult male rats (alcoholic rats) received an ethanol program, consisting of 4-week-ethanol diet and 3-week-withdrawal per cycle for two cycles. At the end of the diet program, the rats were tested for Rotarod performance and then cerebellum was used to measure PS1 level. Finally, HT22 (mouse hippocampal) cells were exposed to glutamate with or without a p38 inhibitor to measure PS1 level. Results: P38-KO mice were opposite to alcoholic rats in that they showed a decrease and an increase in the level of PS1 protein and mRNA, accompanied by a superior and inferior motoric performance, respectively. Glutamate treatment increased PS1 level in a manner that is attenuated by a p38 inhibitor. Conclusions: These results suggest that p38 activates PS1, contributing to cerebellar deficit of alcoholic rats. They also suggest that p38-PS1 link is readily formed under a hyperexcitatory stress.
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    Treadmill exercise attenuates aging-related bradykinesia: potential involvement of increased nigral GFR-ɑ1 expression and dopamine tissue content
    (2015-03) Arnold, Jennifer C.; Salvatore, Michael F.
    Given the burgeoning increase in our elderly population, lifestyle strategies that mitigate aging-related impairments are essential. Bradykinesia, a cardinal symptom of Parkinson’s disease (PD), also affects up to 30% of the elderly population. Exercise can ameliorate locomotor impairment in PD models and patients, but the neuroanatomical and molecular basis for these effects have not been delineated. Striatal dopamine loss exceeds 80% at onset of bradykinesia in PD, but the greatest loss ever reported in aging humans or animal models is ~50%. Furthermore, exercise-related improvements in locomotor function can occur without significant effects on striatal dopamine in PD models. Here, we hypothesize that an established treadmill exercise regimen could attenuate aging-related bradykinesia (ARB) in conjunction with increased dopamine and the glial cell line-derived neurotrophic factor (GDNF) receptor, GDNF family receptor-alpha 1 (GFR-α1) in the substantia nigra (SN). The rationale for this hypothesis is based on observations that striatal infusion of GDNF in aging models increases locomotor activity and dopamine in the SN, but not striatum. Second, GFR-α1 decreases only in the SN in aging. Third, replenishing the quantity of GFR-α1 lost due to aging increases locomotor activity in combination with increased dopamine and tyrosine hydroxylase (TH) expression in SN, but not striatum, in aged rats. A critical component of this hypothesis is that GDNF, which has been shown to increase following exercise, may also increase GFR-α1 expression. Using our treadmill exercise regimen, we assessed the impact of short- and long-term exercise on ARB and GDNF signaling in aged rats. Our results demonstrate that two rounds of our exercise regimen increased GFR-α1 expression and dopamine in SN of aged rats: a result that reflects the previously reported effect of exogenous GDNF. Notably, a repeated regimen of long-term exercise followed by an equal amount of rest eventually attenuated ARB when compared to non-exercise rats. These studies may be applicable in PD models, in that augmentation of dopamine biosynthesis in SN, instead of striatum, may be an important mechanism of improving locomotor impairment. Finally, our work may delineate molecular targets to enable development of therapeutic strategies that target bradykinesia, particularly in those who may be physically unable or unwilling to exercise.
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    Impact of Hypertension, Diabetes, and Dyslipidemia Comorbidity on Cognition among Hispanic Mexican Americans: An HABLE Study
    (2015-03) Borden, Ashley N.; Johnson, Leigh; Edwards, Melissa; O'Bryant, Sid
    Background: Hypertension, hyperlipidemia, and diabetes mellitus are medical diagnoses that occur at high prevalence rates among the Hispanic Mexican American population. Current research shows that each individual diagnosis is linked to cognitive decline, but this assertion is limited in that these studies have been conducted on Non-Hispanic White populations only. Additionally, an insignificant number of studies have investigated the comorbidity of these diagnoses, and how that may impact risk for cognitive impairment. This study seeks to fill this gap in the literature by determining the association between combinations of these diagnoses and cognitive functioning within a Hispanic Mexican-American population. Methods: Data were analyzed from 537 Mexican American participants who met diagnostic criteria for hypertension, dyslipidemia, and diabetes mellitus (Group 1, one diagnosis, n= 148; Group 2, two diagnoses, n=219; Group 3, three diagnoses, n=170) from the Health and Aging Brain study among Latino Elders (HABLE). Information from each participant was obtained via clinical interview (including medical history, current medications, and health behaviors), informant interview, neuropsychological testing, blood draw, and physical examination. Consensus reviews were conducted weekly to review subject data, and to establish cognitive and medical diagnoses according to national guidelines. Linear regressions analyses were utilized to examine cognitive functioning, measured through the domains of memory and verbal fluency as the dependent variable, with the independent variable consisting of the number of medical diagnoses (one, two, or three). Covariates included age, gender, and education. Results: Those in Group 1 displayed poorer performance on measures of immediate (B[SE]= -2.66[1.05], t-test = -2.52, p-value=0.012) and delayed (B[SE]= -1.59[0.77], t-test= -2.04, p-value= 0.041) memory. Differentially, those in Group 2 showed poorer performance on tasks related to verbal fluency (B[SE]=-2.33[0.80], t-test= -2.88, p-value=0.004) and working memory (B[SE]=-0.59[0.24], t-test=-2.42, p-value=0.016). Group 3, which encompassed all three medical diagnoses, was not significantly related to any of the cognitive domains that were examined. Conclusion: These findings suggest that within the Hispanic Mexican American population, domains of cognitive functioning are differentially affected within each group, with Group 3 showing no significant increased risk for cognitive dysfunction. These findings do not support current research, which suggests a higher and more invariable prevalence of cognitive decline, regardless of the comorbidity of these diagnoses. Additional research is needed to investigate the neurological effects of the biological pathways associated with the varying combination of diseases, which may explain the dissimilarity in associated cognitive function.
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    Epigenetic alterations in Brain tissue and Alzheimer's Disease
    (2015-03) Shewale, Shantanu J.; Barber, Robert C.; Planz, John
    Background: Epigenetic factors such as methylation of DNA have shown to impact the phenotype of a cell and irregular methylation of DNA has been correlated with numerous diseases. DNA methylation has been shown to impact the expression of certain genes associated with AD. Methods: A novel method, methylated DNA immunoprecipitation (MeDIP), is used to study genome wide methylation patterns via high throughput sequencing to assess DNA methylation patterns in brain tissue from individuals diagnosed with AD (N=12) and age matched controls (N=12). MeDIP isolation facilitates an unbiased methylation analysis of the entire human genome by enriching samples for methylated DNA fragments. The MethylMiner kit (Life Technologies) was utilized to precipitate methylated DNA, which was sequenced on the Illumina Hi-seq 2500. In addition, another aliquot will undergo MeDIP and bisulfite treatment. This will allow analysis of methylated cytosines at single base pair resolution across the entire genome. In addition, RNA and miRNA-seq was performed on the Illumina Hi-seq 2500. RNA-seq information obtained provides additional insight on epigenetic impacts on miRNA and RNA levels. Results: Sequence data reveal a genome wide methylation pattern profile, along with gene expression changes that differentiate case from control participants. Conclusions: These data provide insight and help explain a portion of the missing heritability that has yet to be characterized for AD.
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    Toxicity of Amyloid Beta Proteins on SH-SY5Y Cells and Determination of an Optimal Dose of Methylene Blue That is Nontoxic to the SH-SY5Y Cells
    (2015-03) Ebot, James; Yang, Shaohua
    There are many theories that explain the etiology of Alzheimer’s disease but the exact mechanism and pathophysiology of this disease remains unclear. The hallmark of the disease is the identification of amyloid beta plaques in the brains of Alzheimer’s patients during autopsy and tangles of hyper phosphorylated Tau proteins but why and how these compounds mediate their neurotoxicity is still a matter of debate. Knowing the exact mechanisms and the biochemical pathways through which these compounds mediate their neurotoxicity could open a whole new area of research for targeted medical therapy. There have been a lot of studies establishing the neurotoxicity of amyloid beta proteins in different cell lines but there are also studies establishing other factors of neurodegeneration including the tau protein, glutamate toxicity, oxidative stress which makes drawing a conclusion for amyloid beta as the instigator of the disease challenging but there is a general consensus that amyloid beta plays a role in the pathophysiology of Alzheimer’s disease. I investigated the toxicity of amyloid beta proteins on SH-SY5Y cells and also determined an optimal dose of methylene blue that is nontoxic to the SH-SY5Y cells. SH-SY5Y is a human derived cell line used in most labs for scientific research and my decision to use these cells was based on the fact that few studies have been done using these cells to establish amyloid beta toxicity. SH-SY5Y cells were plated on a 96 well plate and allowed to grow to confluency, after which the amyloid beta protein was added to the cell culture and incubated for two days. A cell viability assay was then performed on the cell cultures. My findings showed amyloid beta protein is toxic to SH-SY5Y cells and the toxicity is dose dependent. I was also able to find an optimal dose of methylene blue that is nontoxic to SH-SY5Y cells. Methylene blue has been in clinical use for a long time and some in vivo studies have shown that it can improve cognitive function in rats by increasing the activity of cytochrome c oxidase by up to 25%. With these findings, further investigation into the mechanism through which the amyloid beta protein mediates its toxicity on SH-SY5Y cells can be carried out. Also, using the optimal dose of methylene blue that’s nontoxic to SH-SY5Y cells, I intend to further investigate if methylene blue can reverse the neurotoxic effects of the amyloid beta protein on SH-SY5Y cells.