Resveratrol Induces Brain Resilience Against Alzheimer Neurodegeneration Through Proteostasis Enhancement

Resveratrol is a natural compound that mimics the antioxidant and antiaging effects of caloric restriction, mainly mediated through SIRT1, a deacetylase that induces longevity and neuroprotection. We aimed to analyze the effects of resveratrol on the brain status of control non-transgenic (NoTg) and AD transgenic (3xTg-AD) mice to discern the mechanisms involved in a potential inducement of resilience against age-related neurodegeneration and Alzheimer's disease (AD). Mice were fed with a diet supplemented with 100 mg/kg of resveratrol from 2 months of age during 10 months. Resveratrol administration induced complete protection against memory loss and brain pathology in 3xTg-AD mice, and also induced cognitive enhancement in healthy NoTg mice. Resveratrol improved exploration and reduced anxiety in both mouse strains, indicative of well-being. Resveratrol reduced the presence of Aβ and p-tau pathology in the hippocampus of the 3xTg-AD mouse. Proteostasis analysis showed the following in both NoTg and 3xTg-AD mice: (i) increased levels of the amyloid-degrading enzyme neprilysin, (ii) reduction of the amyloidogenic secretase BACE1, and (iii) increase of proteasome protein levels and enhancement of proteasome activity. Resveratrol also increased AMPK protein levels, then upregulating the SIRT1 pathway, as shown by the activation of PGC-1α and CREB in both mice, resulting in further beneficial changes. Our data demonstrated that resveratrol induces cognitive enhancement and neuroprotection against amyloid and tau pathologies. Improvement of proteostasis by resveratrol, in both healthy and AD mice, suggests that it is a mechanism of brain resilience and defense against neurodegeneration caused by the accumulation of aberrant proteins

Understanding Epigenetics in the Neurodegeneration of Alzheimer's Disease: SAMP8 Mouse Model

Epigenetics is emerging as the missing link among genetic inheritance, environmental influences, and body and brain health status. In the brain, specific changes in nucleic acids or their associated proteins in neurons and glial cells might imprint differential patterns of gene activation that will favor either cognitive enhancement or cognitive loss for more than one generation. Furthermore, derangement of age-related epigenetic signaling is appearing as a significant risk factor for illnesses of aging, including neurodegeneration and Alzheimer's disease (AD). In addition, better knowledge of epigenetic mechanisms might provide hints and clues in the triggering and progression of AD. Intense research in experimental models suggests that molecular interventions for modulating epigenetic mechanisms might have therapeutic applications to promote cognitive maintenance through an advanced age. The SAMP8 mouse is a senescence model with AD traits in which the study of epigenetic alterations may unveil epigenetic therapies against the AD. Keywords: Aging, DNA methylation, epigenetics, histone modification, neurodegeneratio

Antioxidant Molecular Brain Changes Parallel Adaptive Cardiovascular Response to Forced Running in Mice

Physically active lifestyle has huge implications for the health and well-being of people of all ages. However, excessive training can lead to severe cardiovascular events such as heart fibrosis and arrhythmia. In addition, strenuous exercise may impair brain plasticity. Here we investigate the presence of any deleterious effects induced by chronic high-intensity exercise, although not reaching exhaustion. We analyzed cardiovascular, cognitive, and cerebral molecular changes in young adult male mice submitted to treadmill running for eight weeks at moderate or high-intensity regimens compared to sedentary mice. Exercised mice showed decreased weight gain, which was significant for the high-intensity group. Exercised mice showed cardiac hypertrophy but with no signs of hemodynamic overload. No morphological changes in the descending aorta were observed, either. High-intensity training induced a decrease in heart rate and an increase in motor skills. However, it did not impair recognition or spatial memory, and, accordingly, the expression of hippocampal and cerebral cortical neuroplasticity markers was maintained. Interestingly, proteasome enzymatic activity increased in the cerebral cortex of all trained mice, and catalase expression was significantly increased in the high-intensity group; both first-line mechanisms contribute to maintaining redox homeostasis. Therefore, physical exercise at an intensity that induces adaptive cardiovascular changes parallels increases in antioxidant defenses to prevent brain damage

The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer's disease pathology: From antioxidant to epigenetic therapy

While the elderly segment of the population continues growing in importance, neurodegenerative diseases increase exponentially. Lifestyle factors such as nutrition, exercise, and education, among others, influence ageing progression, throughout life. Notably, the Central Nervous System (CNS) can benefit from nutritional strategies and dietary interventions that prevent signs of senescence, such as cognitive decline or neurodegenerative diseases such as Alzheimer's disease and Parkinson's Disease. The dietary polyphenol Resveratrol (RV) possesses antioxidant and cytoprotective effects, producing neuroprotection in several organisms. The oxidative stress (OS) occurs because of Reactive oxygen species (ROS) accumulation that has been proposed to explain the cause of the ageing. One of the most harmful effects of ROS in the cell is DNA damage. Nevertheless, there is also evidence demonstrating that OS can produce other molecular changes such as mitochondrial dysfunction, inflammation, apoptosis, and epigenetic modifications, among others. Interestingly, the dietary polyphenol RV is a potent antioxidant and possesses pleiotropic actions, exerting its activity through various molecular pathways. In addition, recent evidence has shown that RV mediates epigenetic changes involved in ageing and the function of the CNS that persists across generations. Furthermore, it has been demonstrated that RV interacts with gut microbiota, showing modifications in bacterial composition associated with beneficial effects. In this review, we give a comprehensive overview of the main mechanisms of action of RV in different experimental models, including clinical trials and discuss how the interconnection of these molecular events could explain the neuroprotective effects induced by RV

Environmental Enrichment Improves Cognitive Deficits, AD Hallmarks and Epigenetic Alterations Presented in 5xFAD Mouse Model.

Cumulative evidence shows that modifications in lifestyle factors constitute an effective strategy to modulate molecular events related to neurodegenerative diseases, confirming the relevant role of epigenetics. Accordingly, Environmental Enrichment (EE) represents an approach to ameliorate cognitive decline and neuroprotection in Alzheimer's disease (AD). AD is characterized by specific neuropathological hallmarks, such as β-amyloid plaques and Neurofibrillary Tangles, which severely affect the areas of the brain responsible for learning and memory. We evaluated EE neuroprotective influence on 5xFAD mice. We found a better cognitive performance on EE vs. Control (Ct) 5xFAD mice, until being similar to Wild-Type (Wt) mice group. Neurodegenerative markers as β-CTF and tau hyperphosphorylation, reduced protein levels whiles APPα, postsynaptic density 95 (PSD95) and synaptophysin (SYN) protein levels increased protein levels in the hippocampus of 5xFAD-EE mice group. Furthermore, a reduction in gene expression of Il-6, Gfap, Hmox1 and Aox1 was determined. However, no changes were found in the gene expression of neurotrophins, such as Brain-derived neurotrophic factor (Bdnf), Nerve growth factor (Ngf), Tumor growth factor (Tgf) and Nerve growth factor inducible (Vgf) in mice with EE. Specifically, we found a reduced DNA-methylation level (5-mC) and an increased hydroxymethylation level (5-hmC), as well as an increased histone H3 and H4 acetylation level. Likewise, we found changes in the hippocampal gene expression of some chromatin-modifying enzyme, such as Dnmt3a/b, Hdac1, and Tet2. Extensive molecular analysis revealed a correlation between neuronal function and changes in epigenetic marks after EE that explain the cognitive improvement in 5xFAD. Keywords: behavior, cognition, environmental enrichment, epigenetics, APP, Tau, oxidative stress, inflammatio

Peripheral maintenance of the axis SIRT1-SIRT3 at youth level may contribute to brain resilience in middle-aged amateur rugby players

Physical exercise performed regularly is known to improve health and to reduce the risk of age-related diseases. Furthermore, there is some evidence of cognitive improvement in physically active middle-aged and older adults. We hypothesized that long-term physically active middle-aged men may have developed brain resilience that can be detected with the analysis of peripheral blood markers. We aimed to analyze the activation of pathways potentially modulated by physical activity in a cohort of healthy amateur rugby players (n = 24) and control subjects with low physical activity (n = 25) aged 45-65 years. We had previously reported neuropsychological improvement in immediate memory responses in the player group compared to the controls. Here, we tested the expression of selected genes of longevity, inflammation, redox homeostasis, and trophic signaling in whole blood mRNA. Analyses were also performed on blood samples of young (aged 15-25 years) control subjects with low physical activity (n = 21). Physical activity and other lifestyle factors were thoroughly recorded with standardized questionnaires. Interestingly, middle-aged control subjects showed lower levels of expression of SIRT1, SIRT3, CAT, and SOD1 than the young controls, although rugby players maintained the expression levels of these genes at a young-like level. Middle-aged players showed lower levels of IL1B than the non-physically active groups. However, there was a tendency towards a decrease in trophic and transduction factors in middle-aged groups as compared to the young controls. A statistical study of Spearman's correlations supported a positive effect of sporting activity on memory and executive functions, and on peripheral gene expression of SIRT1, SIRT3 and downstream genes, in the middle-aged rugby players. Our results indicate that the SIRT1-SIRT3 axis, and associated neuroprotective signaling, may contribute to the anti-aging resilience of the brain mediated by physical exercise

Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer's Disease

The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with three compounds in clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's Disease (AD). Evaluation of cognitive impairment and pathological hallmarks were used in two models of age-related cognitive decline and AD using three structurally different and potent sEH inhibitors as chemical probes. sEH is upregulated in brains from AD patients. Our findings supported the beneficial effects of central sEH inhibition, regarding reducing cognitive impairment, neuroinflammation, tau hyperphosphorylation pathology and the number of amyloid plaques. This study suggests that inhibition of inflammation in the brain by targeting sEH is a relevant therapeutic strategy for AD

Mecanismos de neuroprotección mediante la modulación de SIRT1

[spa] El aumento de la esperanza de vida poblacional que ha tenido lugar en las últimas décadas, previsiblemente conducirá a un incremento de la incidencia de enfermedades asociadas con la edad, incluyendo la demencia. La principal causa de demencia es la enfermedad de Alzheimer (AD) contra la que no existen tratamientos efectivos, por lo que se está convirtiendo en un obstáculo para el envejecimiento saludable. Es de gran interés científico y social la búsqueda de nuevas dianas terapéuticas para disminuir el riesgo de AD y la severidad de la patología una vez desencadenada. En esta tesis se estudia la vía de longevidad y neuroprotección de SIRT1, una desacetilasa que tiene una actividad antienvejecimiento en cuanto a su contribución al mantenimiento de la fisiología celular. Estudios previos sugieren que puede ser eficaz contra aspectos de la patología neuronal de tipo amiloide y tau que cursa en AD. El objetivo general es definir la vía de SIRT1 como diana terapéutica en AD. El estudio se ha llevado a cabo en ratones 3xTg-AD y cultivos neuronales de estos ratones, como modelos experimentales in vivo e in vitro, respectivamente, de AD. La investigación se ha desarrollado en los siguientes tres estudios: Estudio 1: Se demuestra que la sobreexpresión de SIRT1 mediante la inyección de un vector lentiviral en el hipocampo de ratones 3xTg-AD induce protección de la pérdida cognitiva, ya que los ratones 3xTg- SIRT1 muestran memoria y capacidad de aprender durante los diferentes ensayos de comportamiento. Los análisis muestran que los ratones 3xTg-SIRT1 favorecen la vía no amiloidogénica de la proteína APP mediante el aumento de la expresión de ADAM10. El incremento de los niveles de los factores neurotróficos BDNF y VEGF analizados en el hipocampo también adquiere importancia en la protección cognitiva ya que favorecen la plasticidad neuronal. Es notable el hecho de que el efecto pro-cognitivo inducido por la sobreexpresión de SIRT1 se detecta también en ratones control. Estudio 2: Mediante los cultivos de neuronas 3xTg-SIRT1 se demuestra un aumento de las vías de degradación por las que disminuye el péptido Aβ, con aumento de la proteína IDE y del sistema ubiquitina- proteasoma. La activación de la vía no amiloidogénica de procesamiento de la APP promovida por SIRT1 contribuye a la disminución de Aβ. La diminución de p-tau se produce a través de la desacetilación de la proteína ac-tau que induce su degradación por el proteasoma. El aumento de los niveles de factores neurotróficos y la mejora de la arborización es otro de los mecanismos implicados en la neuroprotección inducida por SIRT1 y se observa en neuronas 3xTg-AD y en neuronas control. Igualmente destacable es el hecho que la activación de las vías de proteólisis de proteínas anormales se detecta también en las neuronas control. Estudio 3: El ensayo de dos moléculas activadoras de SIRT1 que pueden ingerirse con la dieta, resveratrol y melatonina, ha demostrado sus efectos neuroprotectores en ratones 3xTg-AD. Los análisis realizados muestran que el tratamiento con melatonina o con resveratrol induce una actividad recuperadora de la capacidad cognitiva y neuroprotectora de la patología AD. Los mecanismos estudiados demuestran la implicación de la vía SIRT1. En esta tesis se ha demostrado que la activación farmacológica de SIRT1 puede ser una buena estrategia terapéutica para prevenir y proteger contra los procesos neurodegenerativos, ya que los beneficios incluyen: (i) la total preservación de la capacidad cognitiva, (ii) una extraordinaria protección contra la patología amiloide y tau, (iii) activación de las vías de proteólisis de proteínas anormales, y (iv) activación del neurotrofismo.[eng] The progressive gain of human life expectancy has led to an increase of the incidence of age-related neurodegenerative diseases. Alzheimer’s disease (AD) is the most common cause of dementia, so is becoming an obstacle to healthy aging. SIRT1 is a member of the sirtuin family of enzymes that promotes longevity and cell survival through the regulation of the acetylation homeostasis of key proteins. This thesis examines the SIRT1 pathway as a therapeutic target in AD. The study has been carried out in the AD mouse model 3xTg-AD and its control strain, and in neuronal cultures of these mice. SIRT1 overexpression by injecting a lentiviral vector into the hippocampus of 3xTg-AD mice induced protection against cognitive loss. Results showed that SIRT1 favors the non-amyloidogenic pathway by increasing ADAM10 expression. Also, the increased levels of neurotrophic factors promoted neuronal plasticity and cognitive protection. The pro-cognitive effect induced by SIRT1 overexpression was also detected in the control mice. SIRT1 overexpression in the 3xTg-AD neuron cultures demonstrated an increase in the Aβ degradation pathways, with an increase in the IDE protein and in the ubiquitin-proteasome system. Activation of the non-amyloidogenic pathway promoted by SIRT1 contributed to the decrease of Aβ. The decrease of p-tau occurs through the deacetylation of the ac-tau protein, which induces its degradation by the proteasome. The activation of abnormal protein proteolysis pathways were also detected in control neurons. Increased levels of neurotrophic factors and improved arborization were induced by SIRT1 in AD-like and in control neurons. The assay of resveratrol and melatonin, SIRT1 activators that can be ingested with the diet, demonstrated the neuroprotective effects in 3xTg-AD mice. Treatment with melatonin or resveratrol induced an activity that recovered the cognitive function and decreased AD pathology. The mechanisms studied demonstrated the involvement of the SIRT1 pathway. This thesis has shown that the pharmacological activation of SIRT1 may be a good therapeutic strategy to prevent and protect against neurodegenerative processes, since the benefits include: (i) total preservation of cognitive ability, (ii) protection against amyloid and tau pathology, (iii) enhancement of cell proteostatic mechanisms, and (iv) activation of neurotrophism

Long-term exercise training improves memory in middle-aged men and modulates peripheral levels of BDNF and Cathepsin B.

Aging is accompanied by a decline in memory and other brain functions. Physical exercise may mitigate this decline through the modulation of factors participating in the crosstalk between skeletal muscle and the brain, such as neurotrophins and oxidative stress parameters. We aimed to determine whether long term exercise training (35 ± 15 years) promotes memory maintenance in middle-aged men, and to characterize the changes in neurotrophic factors and lipid oxidation markers in peripheral blood samples in both middle-aged and young men. The neuropsychological analysis showed significant improvements in memory through the Free and Cued Immediate Recall tests, in the middle-aged trained individuals when compared to the sedentary ones. We found a significant decrease in the resting serum BDNF and plasma Cathepsin B (CTSB) levels in the trained groups at both middle and young ages. BDNF and CTSB levels were inversely correlated with weekly hours of exercise. We also found a significant decrease in plasma malondialdehyde, an index of lipid peroxidation, in middle-aged and young trained subjects. The positive impact of long-term exercise training by delaying the onset of physiological memory loss and the associated neurotrophic and redox peripheral modulation, suggests the effectiveness of exercise as preventive strategy against age-related memory loss and neurodegeneration

Neuroprotective Epigenetic Changes Induced by Maternal Treatment with an Inhibitor of Soluble Epoxide Hydrolase Prevents Early Alzheimer's Disease Neurodegeneration

Modulation of Alzheimer's disease (AD) risk begins early in life. During embryo development and postnatal maturation, the brain receives maternal physiological influences and establishes epigenetic patterns that build its level of resilience to late-life diseases. The soluble epoxide hydrolase inhibitor N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl] urea (TPPU), reported as ant-inflammatory and neuroprotective against AD pathology in the adult 5XFAD mouse model of AD, was administered to wild-type (WT) female mice mated to heterozygous 5XFAD males during gestation and lactation. Two-month-old 5XFAD male and female offspring of vehicle-treated dams showed memory loss as expected. Remarkably, maternal treatment with TPPU fully prevented memory loss in 5XFAD. TPPU-induced brain epigenetic changes in both WT and 5XFAD mice, modulating global DNA methylation (5-mC) and hydroxymethylation (5-hmC) and reducing the gene expression of some histone deacetylase enzymes (Hdac1 and Hdac2), might be on the basis of the long-term neuroprotection against cognitive impairment and neurodegeneration. In the neuropathological analysis, both WT and 5XFAD offspring of TPPU-treated dams showed lower levels of AD biomarkers of tau hyperphosphorylation and microglia activation (Trem2) than the offspring of vehicle-treated dams. Regarding sex differences, males and females were similarly protected by maternal TPPU, but females showed higher levels of AD risk markers of gliosis and neurodegeneration. Taken together, our results reveal that maternal treatment with TPPU impacts in preventing or delaying memory loss and AD pathology by inducing long-term modifications in the epigenetic machinery and its marks