Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats.
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ABSTRACT:
SUBMITTER: Chai GS
PROVIDER: S-EPMC5562564 | biostudies-other | 2014 Dec
REPOSITORIES: biostudies-other
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Project description:Oxymatrine (OMT) is the major quinolizidine alkaloid extracted from the root of Sophora flavescens Ait (the Chinese herb Kushen) and exhibits diverse pharmacological actions. In this work we investigated the effects of OMT on diabetes-associated cognitive decline (DACD) in a rat model of diabetes and explored the mechanisms of action.Male Wistar rats were injected with streptozotocin (65 mg/kg, ip) once to induce diabetes. The rats were then treated with vehicle or OMT (60 or 120 mg/kg per day, ip) for 7 weeks. Memory function was assessed using Morris water maze test. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), NF-κB p65 unit, TNF-α, IL-1β and caspase-3 in the cerebral cortex and hippocampus were quantified.The diabetic rats exhibited markedly reduced body weight and increased plasma glucose level. The memory function of the rats assessed using Morris water maze test showed significant reduction in the percentage of time spent in the target quadrant and the number of times crossing the platform, coupled with markedly prolongation of escape latency and mean path length. Moreover, the rats showed oxidative stress (significantly increased MDA, decreased SOD and reduced GSH levels), as well as significant increases of NF-κB p65 unit, TNF-α, IL-1β and caspase-3 levels in the cerebral cortex and hippocampus. Chronic treatment with OMT dose-dependently reversed these behavioral, biochemical and molecular changes in the diabetic rats. However, the swimming speed had no significant difference among the control, diabetic and OMT-treated diabetic rats.Chronic treatment with OMT alleviates diabetes-associated cognitive decline in rats, which is associated with oxidative stress, inflammation and apoptotic cascades.
| S-EPMC4647892 | biostudies-other
Project description:ImportanceIndicators of early-life cognitive enrichment (ELCE) have been associated with slower cognitive decline and decreased dementia in late life. However, the mechanisms underlying this association have not been elucidated.ObjectiveTo examine the association of ELCE with late-life Alzheimer disease (AD) and other common dementia-related pathological changes.Design, setting, and participantsThis clinical-pathological community-based cohort study, the Rush Memory and Aging Project, followed up participants before death for a mean (SD) of 7.0 (3.8) years with annual cognitive and clinical assessments. From January 1, 1997, through June 30, 2019, 2044 participants enrolled, of whom 1018 died. Postmortem data were leveraged from 813 participants. Data were analyzed from April 12, 2019, to February 20, 2020.ExposuresFour indicators of ELCE (early-life socioeconomic status, availability of cognitive resources at 12 years of age, frequency of participation in cognitively stimulating activities, and early-life foreign language instruction) were obtained by self-report at the study baseline, from which a composite measure of ELCE was derived.Main outcomes and measuresA continuous global AD pathology score derived from counts of diffuse plaques, neuritic plaques, and neurofibrillary tangles.ResultsThe 813 participants included in the analysis had a mean (SD) age of 90.1 (6.3) years at the time of death, and 562 (69%) were women. In a linear regression model controlled for age at death, sex, and educational level, a higher level of ELCE was associated with a lower global AD pathology score (estimate, -0.057; standard error, 0.022; P = .01). However, ELCE was not associated with any other dementia-related pathological changes. In addition, a higher level of ELCE was associated with less cognitive decline (mean [SD], -0.13 [0.19] units per year; range, -1.74 to 0.85). An indirect effect through AD pathological changes constituted 20% of the association between ELCE and the rate of late-life cognitive decline, and 80% was a direct association.Conclusions and relevanceThese findings suggest that ELCE was associated with better late-life cognitive health, in part through an association with fewer AD pathological changes.
| S-EPMC7325069 | biostudies-literature
Project description:Alzheimer's disease is an irreversible neurodegenerative disorder that is characterized by the abnormal aggregation of amyloid-β into neurotoxic oligomers and plaques. Although many disease-modifying molecules are currently in Alzheimer clinical trials, a small molecule that inhibits amyloid-β aggregation and ameliorates the disorder has not been approved to date. Herein, we report the effects of a potent small molecule, 6-methoxy-2-(4-dimethylaminostyryl) benzofuran (KMS88009), that directly disrupts amyloid-β oligomerization, preserving cognitive behavior when used prophylactically and reversing declines in cognitive behavior when used therapeutically. KMS88009 exhibited excellent pharmacokinetic profiles with extensive brain uptake and a high level of safety. When orally administered before and after the onset of Alzheimer's disease symptoms, KMS88009 significantly reduced assembly of amyloid-β oligomers and improved cognitive behaviors in the APP/PS1 double transgenic mouse model. The unique dual mode of action indicates that KMS88009 may be a powerful therapeutic candidate for the treatment of Alzheimer's disease.
| S-EPMC3997483 | biostudies-literature
Project description:Preterm birth is a principal cause of neurological disability later in life, including cognitive and behavioral deficits. Notably, cognitive impairment has greater impact on quality of life than physical disability. Survivors of preterm birth commonly have deficits of executive function. Difficulties with tasks and planning complexity correlate positively with increasing disability. To overcome these barriers for children born preterm, preclinical and clinical studies have emphasized the importance of neurorestoration. Erythropoietin (EPO) is a endogenous cytokine with multiple beneficial mechanisms of action following perinatal brain injury. While most preclinical investigations have focused on pathology and molecular mechanisms, translational studies of repair using clinically viable biobehavioral biomarkers are still lacking. Here, using an established model of encephalopathy of prematurity secondary to placental insufficiency, we tested the hypothesis that administration of EPO in the neonatal period would attenuate deficits in recognition memory and cognitive flexibility in adult rats of both sexes. We assessed cognition and executive function in two ways. First, using the classic test of novel object recognition and second, using a touchscreen platform. Touchscreen testing allows for rigorous testing of cognition and executive function in preclinical and clinical scenarios. Data show that adult rats exhibit deficits in recognition memory and cognitive flexibility following in utero placental insufficiency. Notably, neonatal treatment of EPO attenuates these deficits in adulthood and facilitates functional repair. Together, these data validate EPO neurorestoration using a clinically relevant outcome measure and support the concept that postnatal treatment following in utero injury can improve cognition and executive function through adulthood.
| S-EPMC10097461 | biostudies-literature
Project description:Alzheimer disease (AD), a progressive neurodegenerative disorder, is characterized by cognitive decline and the accumulation of senile plaques in the brain. Amyloid β protein (Aβ) in the plaques is thought to be responsible for the memory loss in AD patients. [Gly14]-humanin (HNG), a derivative of humanin (HN), has much stronger neuroprotective effects than natural HN in vitro. However, clarification of the Aβ active center and the neuroprotective mechanism of HN still need in vivo evidence. The present study first compared the in vivo biological effects of three Aβ fragments (1-42, 31-35, and 35-31) on spatial memory in rats, and investigated the neuroprotective effects and molecular mechanisms of HNG. The results showed that intrahippocampal injection of Aβ1-42 and Aβ31-35 almost equally impaired spatial learning and memory, but the reversed sequence Aβ35-31 did not have any effect; a high dose of Aβ31-35 (20 nmol) produced a more detrimental response than a low dose (2 nmol); Aβ31-35 injection also disrupted gene and protein expression in the hippocampus, with up-regulation of caspase3 and down-regulation of STAT3; pretreatment with HNG not only protected spatial memory but also rescued STAT3 from Aβ-induced disruption; and the neuroprotective effects of HNG were effectively counteracted by genistein, a specific tyrosine kinase inhibitor. These results clearly show that sequence 31-35 in Aβ is the shortest active center responsible for the neurotoxicity of Aβ from molecule to behavior; and HNG protects spatial learning and memory in rats against Aβ-induced insults; and probably involves the activation of tyrosine kinases and subsequent beneficial modulation of STAT3 and caspase3.
| S-EPMC5563781 | biostudies-other
Project description:Plaques containing the aggregated beta-Amyloid (Abeta) peptide in the brain are the main indicators of Alzheimer's disease. Fibrils, the building blocks of plaques, can also be produced in vitro and consist of a regular arrangement of the peptide. The initial steps of fibril formation are not well understood and could involve smaller aggregates (oligomers) of Abeta. Such oligomers have even been implicated as the toxic agents. Here, a method to study oligomers on the time scale of aggregation is suggested. We have labeled the 40 residue Abeta peptide variant containing an N-terminal cysteine (cys-Abeta) with the MTSL [1-oxyl-2,2,5,5-tetramethyl-Delta-pyrroline-3-methyl] methanethiosulfonate spin label (SL-Abeta). Fibril formation in solutions of pure SL-Abeta and of SL-Abeta mixed with Abeta was shown by Congo-red binding and electron microscopy. Continuous-wave 9 GHz electron paramagnetic resonance reveals three fractions of different spin-label mobility: one attributed to monomeric Abeta, one to a multimer (8-15 monomers), and the last one to larger aggregates or fibrils. The approach, in principle, allows detection of oligomers on the time scale of aggregation.
| S-EPMC2779421 | biostudies-literature
Project description:BackgroundBrain amyloid deposition is one of the main pathological characteristics of Alzheimer's disease (AD). Soluble oligomers formed during the process that causes ?-amyloid (A?) to aggregate into plaques are considered to have major neurotoxicity. Currently, drug development for the treatment of Alzheimer's disease has encountered serious difficulties. Our newly proposed solution is to accelerate the aggregation of A? to reduce the amount of cytotoxic A? oligomers in brain tissue. This strategy differs from the existing strategy of reducing the total A? content and the number of amyloid plaques.MethodIn this study, we screened a small library and found that a flavonoid compound (ZGM1) promoted the aggregation of ?-amyloid (A?). We further verified the binding of ZGM1 to A?42 using a microscale thermophoresis (MST) assay. Subsequently, we used dot blotting (DB), transmission electron microscopy (TEM), and thioflavin T fluorescence (ThT) measurements to study the aggregation of A? under the influence of ZGM1. By using cell experiments, we determined whether ZGM1 can inhibit the cytotoxicity of A?. Finally, we studied the protective effects of ZGM1 on cognitive function in APPswe/PS1 mice via behavioral experiments and measured the number of plaques in the mouse brain by thioflavin staining.ResultsZGM1 can bind with A? directly and mediate a new A? assembly process to form reticular aggregates and reduce the amount of A? oligomers. Animal experiments showed that ZGM1 can significantly improve cognitive dysfunction and that A? plaque deposition in the brain tissue of mice in the drug-administered group was significantly increased.ConclusionOur research suggests that promoting A? aggregation is a promising treatment method for AD and deserves further investigation.
| S-EPMC6918606 | biostudies-literature
Project description:Pyroglutamate-modified Aβ peptides at amino acid position three (Aβ(pE3-42)) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). Aβ(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work was to study the direct effect of elevated Aβ(pE3-42) levels on ongoing AD pathology using transgenic mouse models. To this end, we generated a novel mouse model (TBA42) that produces Aβ(pE3-42). TBA42 mice showed age-dependent behavioral deficits and Aβ(pE3-42) accumulation. The Aβ profile of an established AD mouse model, 5XFAD, was characterized using immunoprecipitation followed by mass spectrometry. Brains from 5XFAD mice demonstrated a heterogeneous mixture of full-length, N-terminal truncated, and modified Aβ peptides: Aβ(1-42), Aβ(1-40), Aβ(pE3-40), Aβ(pE3-42), Aβ(3-42), Aβ(4-42), and Aβ(5-42). 5XFAD and TBA42 mice were then crossed to generate transgenic FAD42 mice. At 6 months of age, FAD42 mice showed an aggravated behavioral phenotype compared with single transgenic 5XFAD or TBA42 mice. ELISA and plaque load measurements revealed that Aβ(pE3) levels were elevated in FAD42 mice. No change in Aβ(x)(-42) or other Aβ isoforms was discovered by ELISA and mass spectrometry. These observations argue for a seeding effect of Aβ(pE-42) in FAD42 mice.
| S-EPMC3318696 | biostudies-literature
Project description:As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes.To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study).With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies.For the 2 studies that collected data on A? levels (ADNI and AIBL), we estimate decline in a preclinical AD "A?-positive" placebo group and compare them with an "A?-negative" group. For the study that did not include data on A? levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-?4 and by clinical progression.In ADNI, A?-positive participants showed more decline than did A?-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, -1.239 [0.522] [95% CI, -2.263 to -0.215]; P?=?.02). In AIBL, the mean (SE) difference is significant at both 18 months (-1.009 [0.406] [95% CI, -1.805 to -0.213]; P?=?.01) and 36 months (-1.404 [0.452] [95% CI, -2.290 to -0.519]; P?=?.002). In the ADCS-PI study, APOE-?4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, -0.742 [0.294] [95% CI, -1.318 to -0.165]; P?=?.01) and 36 months (-1.531 [0.469] [95% CI, -2.450 to -0.612]; P?=?.001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, -4.471 [0.702] [95% CI, -5.848 to -3.094]; P?<?.001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% ? level, we project 80% power to detect effects in the range of ??=?0.467 to 0.733 on the ADCS-PACC.Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials.
| S-EPMC4439182 | biostudies-literature
Project description:The assembly of tau protein into abnormal filaments and brain cell degeneration are characteristic of a number of human neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Several murine models have been generated to better understand the mechanisms contributing to tau assembly and neurodegeneration. Taking advantage of the more elaborate central nervous system and higher cognitive abilities of the rat, we generated a model expressing the longest human tau isoform (2N4R) with the P301S mutation. This transgenic rat line, R962-hTau, exhibits the main features of human tauopathies, such as: age-dependent increase in inclusions comprised of aggregated-tau, neuronal loss, global neurodegeneration as reflected by brain atrophy and ventricular dilation, alterations in astrocytic and microglial morphology, and myelin loss. In addition, substantial deficits across multiple memory and learning paradigms, including novel object recognition, fear conditioning and Morris water maze tasks, were observed at the time of advanced tauopathy. These results support the concept that progressive tauopathy correlates with brain atrophy and cognitive impairment.
| S-EPMC6597947 | biostudies-literature