Reverse Memory Research Articles

DigiSpan: Development and Evaluation of a Computer-Based, Adaptive Test of Short-Term Memory and Working Memory.

This article describes DigiSpan, a new computer-controlled auditory test of forward and reverse digit span, designed to be administered by clinicians, and presents normative and test-retest reliability data for adults. DigiSpan mimics conventional live-voice tests in that it commences with trials that ascend in length until a stopping criterion is met, giving rise to a conventional scaled score. It then administers five additional adaptive trials, the length of which depends on the correctness of the response to the previous trial. Each of these two segments of the measurement gives rise to a scaled score. The ascending and adaptive scores are averaged to give an overall score and subtracted to produce an internal measure of consistency, and hence reliability. Young adults with an Mage of 25 years (N = 163) were tested, of whom 65 were retested on a separate day. The scaled scores from the conventional ascending trials were highly consistent with existing normative data based on live-voice tests. Combination of the conventional scaled score with a scaled score based on the adaptive trials led to 44% reduction in error variance for forward memory span and 20% reduction for reverse memory span. The average of these (32%) is similar to but (insignificantly) less than the 42% reduction in error variance that can be predicted based on adding the five adaptive trials. Replacing live-voice production of digits by a clinician with recorded, computer-controlled production has not affected the difficulty of the test. Adding five additional trials around the sequence length that a test participant can just remember has produced a decrease in measurement error. In addition, the availability of separate scaled scores for the ascending and adaptive phases enables the reliability of the combined score to be checked, for both forward and reverse measurements. The combination of standardized delivery, increased accuracy, internal reliability check, and fast automated scoring makes the test highly suitable for clinical use.

Behavioral and transcriptional effects of carnosine in the central ring ganglia of the pond snail Lymnaea stagnalis.

Carnosine is a naturally occurring endogenous dipeptide with well-recognized anti-inflammatory, antioxidant, and neuroprotective effects at the central nervous system level. To date, very few studies have been focused on the ability of carnosine to rescue and/or enhance memory. Here, we used a well-known invertebrate model system, the pond snail Lymnaea stagnalis, and a well-studied associative learning procedure, operant conditioning of aerial respiration, to investigate the ability of carnosine to enhance long-term memory (LTM) formation and reverse memory obstruction caused by an immune challenge (i.e., lipopolysaccharide [LPS] injection). Exposing snails to 1 mM carnosine for 1 h before training in addition to enhancing memory formation resulted in a significant upregulation of the expression levels of key neuroplasticity genes (i.e., glutamate ionotropic receptor N-methyl-d-aspartate [NMDA]-type subunit 1-LymGRIN1, and the transcription factor cAMP-response element-binding protein 1-LymCREB1) in snails' central ring ganglia. Moreover, pre-exposure to 1 mM carnosine before an LPS injection reversed the memory deficit brought about by inflammation, by preventing the upregulation of key targets for immune and stress response (i.e., Toll-like receptor 4-LymTLR4, molluscan defense molecule-LymMDM, heat shock protein 70-LymHSP70). Our data are thus consistent with the hypothesis that carnosine can have positive benefits on cognitive ability and be able to reverse memory aversive states induced by neuroinflammation.

Astragaloside IV as a Memory-Enhancing Agent: In Silico Studies with In Vivo Analysis and Post Mortem ADME-Tox Profiling in Mice.

Many people around the world suffer from neurodegenerative diseases associated with cognitive impairment. As life expectancy increases, this number is steadily rising. Therefore, it is extremely important to search for new treatment strategies and to discover new substances with potential neuroprotective and/or cognition-enhancing effects. This study focuses on investigating the potential of astragaloside IV (AIV), a triterpenoid saponin with proven acetylcholinesterase (AChE)-inhibiting activity naturally occurring in the root of Astragalus mongholicus, to attenuate memory impairment. Scopolamine (SCOP), an antagonist of muscarinic cholinergic receptors, and lipopolysaccharide (LPS), a trigger of neuroinflammation, were used to impair memory processes in the passive avoidance (PA) test in mice. This memory impairment in SCOP-treated mice was attenuated by prior intraperitoneal (ip) administration of AIV at a dose of 25 mg/kg. The attenuation of memory impairment by LPS was not observed. It can therefore be assumed that AIV does not reverse memory impairment by anti-inflammatory mechanisms, although this needs to be further verified. All doses of AIV tested did not affect baseline locomotor activity in mice. In the post mortem analysis by mass spectrometry of the body tissue of the mice, the highest content of AIV was found in the kidneys, then in the spleen and liver, and the lowest in the brain.

The Effect of FTY720 on Sphingolipid Imbalance and Cognitive Decline in Aged EFAD Mice.

During Alzheimer's disease (AD) progression, there is a decline in the bioactive sphingolipid sphingosine-1-phosphate (S1P). Previous research showed that FTY720, an S1P mimetic, prevented cognitive decline and reduced ceramide levels in transgenic mice with familial AD carrying the human APOE4 gene (E4FAD) at 6-7 months of age. The objective of this study is to explore the protective effects of FTY720 at late-stage AD. Male mice aged 9.5 to 10.5 months were orally administered FTY720 (0.1 mg/kg) via oral gavage for 6 weeks. A pre-test of water maze was used for evaluating the pathological status. After 4 weeks of administration, memory, locomotion, and anxiety were assessed. Cortex samples were analyzed for amyloid-β (Aβ) and sphingolipid levels. Compared with APOE3 mice, APOE4, E3FAD and E4FAD mice exhibited significant memory deficits. After 6 weeks administration, FTY720 did not alleviate memory deficits in EFAD mice. Lipid analysis revealed that S1P was significantly reduced in EFAD mice (E3FAD or E4FAD) compared to controls (APOE3 and APOE4). Ceramide level alterations were predominantly dependent on APOE isoforms rather than AD transgenes. Interestingly, Cer (d18 : 1/22 : 1) was elevated in APOE4 mice compared to APOE3, and FTY720 reduced it. E4FAD and APOE4 mice exhibited significant spatial memory deficits and higher ceramide concentrations compared to APOE3 mice. FTY720 did not reverse memory deficits in E4FAD and APOE4 mice but reduced specific ceramide species. This study provides insights into the association between sphingolipids and APOE4 in advanced AD stages, exploring potential therapeutic targeting of sphingolipid metabolism.

Combined effect of prebiotic and probiotic strains restores cognitive impairment via attenuating synaptosis in the hippocampus of mice fed with high fat diet and streptozotocin diabetes‐induced dementia

AbstractBackgroundDementia is known as neurodegenerative disease which causes decline in the cognitive domains of memory and thinking, leading to memory loss of an individual especially the aged. Diabetes mellitus causes brain structure changes and cognitive decline, and it has been estimated that diabetes doubles the risk for dementia. Probiotics combined with prebiotics on the other hand, seem to have a positive effect and reverse memory lossMethodThis study employed ninety (90) male bulb/c albino mice weighing between 25 and 28 grams (n = 15). Animals were housed in plastic cages at room temperature under good hygienic conditions, had free access to animal pellets and water ad libitum. Mice were fed with a high fat diet to imitate obesity after which Diabetes was induced by one administration of STZ (50 mg/kg, IP) freshly dissolved in citrate buffer following an overnight fasting on 22nd day. Probiotic strains and Prebiotics were administered with prepared suspension containing 107 and 109 CFU/ml of probiotics and prebiotics (3mg and 5 mg) body weight orally for pretreatment and posttreatment after streptozotocin induction.ResultResults from this study shown that there was a significant decrease in glucose levels of animals treated with probiotics and prebiotics combined supplementation in both pretreatment (HFDS +109 CFU/ml + 5 mg) and post‐treatment group (HFDS +109 CFU/ml + 5 mg) with insulin resistance. AChE levels significantly reduced at the combined probiotics and prebiotics pretreatment (HFDS +109 CFU/ml + 5 mg) and post‐treatment group (HFDS +109 CFU/ml + 5 mg). With relation to BDNF gene expression analysis, combined probiotics and prebiotics showed high expression of the BDNF gene in the combined probiotics and prebiotics pretreatment (HFDS +109 CFU/ml + 5 mg) and post‐treatment group (HFDS +109 CFU/ml + 5 mg). Administration of combined probiotics and prebiotics improved memory and learning, insulin resistance, animal weight, glucose levels and BDNF expression.ConclusionCombined probiotics and prebiotics demonstrated neuroprotective and anti‐neuroinflammatory activity in the experimental animals and was able to attenuate synaptosis and promote synaptogenesis in diabetic mice which started receiving treatment. The combined supplementation also restores cognitive impairment and memory function.

Phytochemical and Therapeutic Potential of Herbal Cognitive Enhancer

Memory is the most significant factor in distinguishing one person from another, as it is necessary to recognise one’s own self. The brain can encode, store, and retrieve information using three different types of memory. Individuals who lack these basic forms of memory are unable to create personal relationships, acquire new knowledge, and perform basic everyday duties. Memory refers to a person’s ability to encode, store, retain, and recall knowledge and past events in his or her brain. Memory gives a person the ability to learn from and adapt to previous experiences, as well as the ability to recall previously taught facts, skills, and habits. Today, poor memory, weak recall, and low retention are all typical issues. Memory deteriorates primarily because of stress and exhaustion. Memory loss, often known as age-related memory impairment, is frequent in those over the age of 40. This could be linked to the loss of hormones and proteins (growth factors) that repair brain cells as people get older. Herbs were employed to improve memory power in India throughout ancient times. Indian and Chinese cultures developed many traditional medicines from herbs to treat diminishing cognition, reverse memory loss, and improve learning power. Nootropic herbs are known for their brain-acting herbs and smart medications, which are derived from their isolated ingredients and aid to improve blood circulation in the brain. The focus of this review is on natural agents and herbs that work as memory enhancers. By using one of the herbs at a time, one can improve his or her memory.

Spatially Distributed Ramp Reversal Memory in VO2

AbstractRamp‐reversal memory has recently been discovered in several insulator‐to‐metal transition materials where a non‐volatile resistance change can be set by repeatedly driving the material partway through the transition. This study uses optical microscopy to track the location and internal structure of accumulated memory as a thin film of VO2 is temperature cycled through multiple training subloops. These measurements reveal that the gain of insulator phase fraction between consecutive subloops occurs primarily through front propagation at the insulator‐metal boundaries. By analyzing transition temperature maps, it is found, surprisingly, that the memory is also stored deep inside both insulating and metallic clusters throughout the entire sample, making the metal‐insulator coexistence landscape more rugged. This non‐volatile memory is reset after heating the sample to higher temperatures, as expected. Diffusion of point defects is proposed to account for the observed memory writing and subsequent erasing over the entire sample surface. By spatially mapping the location and character of non‐volatile memory encoding in VO2, this study results enable the targeting of specific local regions in the film where the full insulator‐to‐metal resistivity change can be harnessed in order to maximize the working range of memory elements for conventional and neuromorphic computing applications.

Ca2+-stimulated ADCY1 and ADCY8 regulate distinct aspects of synaptic and cognitive flexibility.

The type 1 and 8 adenylyl cyclase (ADCY1 and ADCY8) exclusively account for Ca2+-stimulated cyclic AMP (cAMP) production and regulate activity-dependent synaptic modification. In this study, we examined distinct forms of synaptic plasticity in the hippocampus of Adcy1-/- and Adcy8-/- mice. We found that, at the Schaffer collateral-CA1 synapses, while the Adcy8-/- mice displayed normal long-term potentiation (LTP) following various induction protocols with high-frequency stimulation (HFS), the Adcy1-/- mice showed protocol-dependent deficits in LTP. We also found that long-term depression (LTD) requires ADCY1 but not ADCY8. Interestingly, both Adcy1-/- and Adcy8-/- mice showed defective synaptic depotentiation (i.e., activity-dependent reversal of LTP); the deficits in Adcy8-/- mice were dependent on the induction protocol. Examination of spatial memory found that ADCY1 is required for the formation of both initial and reversal memory. ADCY8 is only required for reversal memory formation. These data demonstrate that ADCY1 and ADCY8 play distinct roles in regulating synaptic and cognitive flexibility that involves bidirectional modification of synaptic function.

Norepinephrine Regulates Spatial Memory Consolidation Using Barnes Maze in Male, but Not Female Rats (P1-12.009)

<h3>Objective:</h3> Here, we study the role of NE on spatial learning and memory in rats using a Barnes maze assay. <h3>Background:</h3> The role of norepinephrine (NE) in learning and memory has been extensively studied, yet its contribution to different phases of memory, such as consolidation or updating, remains elusive. <h3>Design/Methods:</h3> We used a specific noradrenergic neurotoxin (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)) to deplete central NE stores. In experiment one, Wistar rats (n=16/sex) were trained to reach a hidden goal box using visual and auditory cues for five days with three trials per day. Rats were administered 50 mg/kg/i.p of DSP-4 or saline ten days prior to training on the Barnes maze assay. DSP-4 mediated reduction of NE, but not serotonin or dopamine, was confirmed using HPLC in several brain regions. In experiment two, using female and male rats (n=16/sex), we replicated results of experiment one by utilizing two trials per day to increase the difficulty of learning the task and extended the findings by utilizing a single probe trial (memory consolidation) and a two-day reversal (memory updating) learning task. <h3>Results:</h3> In experiment one, female and male rats in DSP-4 and saline groups learned the location of the hidden zone, and this was measured by a reduction in latency to reach the goal box. Levels of NE were significantly lower in the dorsal hippocampus, cingulate cortex, and the striatum. Experiment two replicated these results and the subsequent behavioral analysis suggests that only male DSP-4 treated rats increased time spent in the covered hidden zone area during the probe trial. During the reversal learning task, DSP-4 treated males continued to visit the previously hidden platform despite learning the new goal location. <h3>Conclusions:</h3> These data suggest that NE plays a role in regulation of memory consolidation rather than acquisition or memory updating, and this regulation may be sex-specific. <b>Disclosure:</b> Ms. Simpson has nothing to disclose. Dr. Gheidi has nothing to disclose. Dr. Davidson has nothing to disclose. Mr. Yahya has nothing to disclose. Mrs. Trombley has nothing to disclose. Miss Sadik has received personal compensation for serving as an employee of Wayne State University . The institution of Dr. Perrine has received research support from NIH.

Resveratrol and Sir2 Reverse Sleep and Memory Defects Induced by Amyloid Precursor Protein.

Resveratrol (RES), a natural polyphenolic phytochemical, has been suggested as a putative anti-aging molecule for the prevention and treatment of Alzheimer's disease (AD) by the activation of sirtuin 1 (Sirt1/Sir2). In this study, we tested the effects of RES and Sirt1/Sir2 on sleep and courtship memory in a Drosophila model by overexpression of amyloid precursor protein (APP), whose duplications and mutations cause familial AD. We found a mild but significant transcriptional increase of Drosophila Sir2 (dSir2) by RES supplementation for up to 17 days in APP flies, but not for 7 days. RES and dSir2 almost completely reversed the sleep and memory deficits in APP flies. We further demonstrated that dSir2 acts as a sleep promotor in Drosophila neurons. Interestingly, RES increased sleep in the absence of dSir2 in dSir2-null mutants, and RES further enhanced sleep when dSir2 was either overexpressed or knocked down in APP flies. Finally, we showed that Aβ aggregates in APP flies were reduced by RES and dSir2, probably via inhibiting Drosophila β-secretase (dBACE). Our data suggest that RES rescues the APP-induced behavioral deficits and Aβ burden largely, but not exclusively, via dSir2.

Preclinical trials in Alzheimer's disease: Sample size and effect size for behavioural and neuropathological outcomes in 5xFAD mice.

5xFAD transgenic (TG) mice are used widely in AD preclinical trials; however, data on sample sizes are largely unaddressed. We therefore performed estimates of sample sizes and effect sizes for typical behavioural and neuropathological outcome measures in TG 5xFAD mice, based upon data from single-sex (female) groups. Group-size estimates to detect normalisation of TG body weight to WT littermate levels at 5.5m of age were N = 9-15 depending upon algorithm. However, by 1 year of age, group sizes were small (N = 1 -<6), likely reflecting the large difference between genotypes at this age. To detect normalisation of TG open-field hyperactivity to WT levels at 13-14m, group sizes were also small (N = 6-8). Cued learning in the Morris water maze (MWM) was normal in Young TG mice (5m of age). Mild deficits were noted during MWM spatial learning and memory. MWM reversal learning and memory revealed greater impairment, and groups of up to 22 TG mice were estimated to detect normalisation to WT performance. In contrast, Aged TG mice (tested between 13 and 14m) failed to complete the visual learning (non-spatial) phase of MWM learning, likely due to a failure to recognise the platform as an escape. Estimates of group size to detect normalisation of this severe impairment were small (N = 6-9, depending upon algorithm). Other cognitive tests including spontaneous and forced alternation and novel-object recognition either failed to reveal deficits in TG mice or deficits were negligible. For neuropathological outcomes, plaque load, astrocytosis and microgliosis in frontal cortex and hippocampus were quantified in TG mice aged 2m, 4m and 6m. Sample-size estimates were ≤9 to detect the equivalent of a reduction in plaque load to the level of 2m-old TG mice or the equivalent of normalisation of neuroinflammation outcomes. However, for a smaller effect size of 30%, larger groups of up to 21 mice were estimated. In light of published guidelines on preclinical trial design, these data may be used to provide provisional sample sizes and optimise preclinical trials in 5xFAD TG mice.

Role of Irvingia gabonensis Seed Extract in Streptozotocin- Induced Hyperglycemia Memory Deficit in Rodents

The study evaluated the role of Irvingia gabonensis as an antidote for memory loss in streptozotocin (STZ) hyperglycemia. Forty-two rats were grouped into six groups of seven rats. A single dose of STZ (60mg/kg) given intraperitoneally was used to induce hyperglycemia and confirmed after 72 hours with over 200mg/dL of fasting blood glucose. Three doses of extract (100, 200, and 300mg/kg) were used to treat groups C, D, and E, while F received 500mg/kg of the standard drug (metformin). Spatial memory was evaluated using Morris Water Maze, while blood was used to estimate biomarkers. The result showed that hyperglycemia significantly reduced memory with decreased latency compared to control (β) in both the acquisition and reversal memory phases (p≤0.05). The extract improved memory in C, D, and E compared to B (ϒ) and in the standard drug (α) at p≤0.05. Group A showed distinct hippocampal layers with CA 1-4 vital for spatial memory, while group B showed cell vacuolations and hypertrophied neurons with large nuclei. Groups C, D, E, and F showed healthier cells than B. A significant reduction was observed in GST, GOT, and GPX in B compared to the treated groups ((P≤0.05). In conclusion, Irvingia gabonensis seed extract may ameliorate hippocampal alterations and improve learning and memory.

Aniba canelilla (Kunth) Mez essential oil and its primary constituent, 1-nitro-2-phenylethane, inhibits acetylcholinesterase and reverse memory impairment in rodents

Ethnopharmacological relevanceAniba canelilla, distributed in the Amazon region, stands out for its diverse economic and medicinal applications. Studies of the A. canelilla essential oil and its primary constituent, 1-nitro-2-phenylethane, have confirmed its anti-inflammatory, antinociceptive, anti-hypertensive potential, and anticholinesterase, among other therapeutic activities.Aim of the study: In addition, the present work aims to evaluate the potential of oil and NPE in the learning and memory of rodents. Material and methodsThe oil was hydrodistilled and analyzed by GC and GC-MS. The learning and memory action in mice was evaluated through the scopolamine-induced cognitive deficit model, followed by behavioral analysis using Morris's water maze paradigm. ResultsOil provided a yield of 0.5%, and in its chemical composition, 1-nitro-2-phenylethane (NPE) (76.2%) and methyleugenol (19.6%) were identified as primary constituents. Oil fractionation furnished NPE with 99.4%, which was used to evaluate its effects in animal models. Wistar rats were submitted to the mnemonic impairment-scopolamine-induced protocol for 7 days. The oil, NPE, and the positive control donepezil were administered from the 8th to 12th days. Morris water maze results demonstrated that oil and NPE reversed spatial learning and long-term memory similarly induced by muscarinic antagonist scopolamine to donepezil, the positive control. ConclusionThese beneficial effects have led the work to further investigations of the oil and NPE to elucidate their pharmacological mechanism, focusing on the cholinergic pathway of the central nervous system and opening up to the knowledge of other adjacent mechanisms, whose results are still under analysis.

The novel FKBP51‐Hsp90 interaction inhibitor attenuates high‐fat diet induced cognitive impairment

AbstractBackgroundObesity increases the risk of several chronic diseases, such as type 2 diabetes mellitus, insulin resistance, and Alzheimer disease. As one of the co‐chaperones of heat shock protein 90 (Hsp90), FK506‐binding protein 51 (FKBP51) is an important regulator of metabolic and cognitive dysfunction. FKBP51 knockout mice are resistant to diet‐induced obesity, exhibit elevated glucose and insulin tolerance and have less endogenous tau. FKBP51 overexpression preserves tau and impairs spatial reversal learning and memory. Our group has identified a new family of FKBP51 inhibitors that can disrupt FKBP51‐Hsp90 interactions. Previous study has shown that our inhibitors can dose‐dependently reduce lipid accumulation in adipocytes differentiated from primary human mesenchymal stem cells and stimulate neurite outgrowth in differentiated neuroblastoma SH‐SY5Y cells. This study aims to investigate the potential roles of our inhibitors on metabolic and cognitive dysfunction in vivo.MethodsPharmacokinetic studies have been performed at first. Plasma and brain samples were collected and analyzed by liquid chromatography‐mass spectrometry. Male C57BL/6J mice were fed either the control or high‐fat diet (HFD) for 4 weeks and then treated with vehicle or inhibitor E8 (20 mg/kg, s.c.) and their respective diets for another 4 weeks. Behaviors, body composition measuremnets by EchoMRI, fasting glucose/insulin detections and glucose/insulin tolerance tests were performed during the last week. Hippocampus was collected for western blot, RNA sequencing and quantitative real‐time PCR analysis.ResultsAfter subcutaneous injection, E8 can be quickly absorbed into the blood and penetrate the blood‐brain barrier. In HFD model, E8 can attenuate the impairment of locomotor activity and short‐term memory. But it could neither reduce body weight gain nor improve insulin sensitivity and glucose/insulin tolerance. In the hippocampus, E8 reduces the elevated p‐tau (Ser214)/tau levels induced by HFD but does not show any effects on insulin signaling. It suggests that E8 reverses the behavioral impairments independently of metabolic regulation in vivo. The underlying mechanisms were further investigated by RNA sequencing and quantitative real‐time PCR analysis.ConclusionWe showed that inhibiting FKBP51‐Hsp90 interactions with small molecules provides novel therapeutic targets on cognitive dysfunction in obesity.

Universality and microstrain origin of the ramp reversal memory effect

The recently discovered ramp reversal memory (RRM) is a nonvolatile memory effect observed in correlated oxides with temperature-driven insulator--metal transitions (IMT). It appears as a resistance increase at predefined temperatures that are set or erased by simple heating--cooling (i.e., ramp reversal) protocols. Until now RRM was measured for two materials: ${\mathrm{VO}}_{2}$ and ${\mathrm{NdNiO}}_{3}$. A heuristic model suggests that the RRM is caused by a local transition temperature increase at boundaries of spatially separated metallic and insulating domains during ramp reversal. However, there is no experimental measure of the magnitude of the effect, which is crucial for the development of a theoretical account of the RRM. Here we show that ${\mathrm{V}}_{2}{\mathrm{O}}_{3}$ also shows RRM, including all related features, highlighting the generality of the effect. Moreover, an analysis of the RRM as an effective (average) increase of the critical temperature provides a quantitative measure of its magnitude as a function of temperature and ramp reversal protocols. We provide clear evidence that the RRM is the outcome of a local increase in transition temperature of the microscopic-scale phase boundaries that are created during temperature ramp reversal (from heating to cooling) within the insulator--metal phase coexistence regime.

Protective effect of Gastrodia elata blume ameliorates simulated weightlessness-induced cognitive impairment in mice

During the long-term orbital flight, exposure to microgravity negatively affects the astronauts' development of cognition, characterized by learning and memory decline. Gastrodia elata Blume (GEB) has a significant protective effect on cognitive impairment and has been used in Asia for centuries as a functional product. A previous study demonstrated that GEB could improve memory loss in mice caused by circadian rhythm disorders. However, the effects of GEB on cognitive dysfunction caused by weightless environments have not been investigated. In this study, mice received daily treatment with GEB (0.5, 1 g·kg−1d−1, i.g) and Huperzine A(Hup, 0.1 mg·kg−1d−1, i.g) orally until the end of the behavioral test (New object recognition test (NORT). Malondialdehyde (MDA) and nitric oxide (NO) levels were detected by kits, and expression of brain-derived neurotrophic factor (BDNF), protein kinase B (AKT), phosphorylated Akt (P-AKT), synaptophysin (SYN) and postsynaptic density 95(PSD95) in hippocampus were detected by western blotting. The results show that administration of GEB (0.5, 1 g·kg−1d−1, i.g) and Hup (0.1 mg·kg−1d−1, i.g) remarkably reverse HLS-induced learning and behavioral memory disorders, which were associated with significant changes in MDA and NO levels. Additionally, the protein expressions of BDNF, P-AKT/AKT, SYN, and PSD95 were significantly increased in the hippocampus. In summary, our findings will improve the reference for developing GEB as a functional product that improves memory decline.

24-OR: Podocyte Targeted Pyruvate Kinase M2 (PKM2) Activation Normalized Glomerular VEGF Expression, Mitochondrial Function, Fuel Metabolism, and Diabetic Nephropathy

Diabetic nephropathy (DN) is the result of abnormal systemic and local changes in metabolism and hemodynamics. We have reported that many glycolytic enzymes, such as pyruvate kinase M2 (PKM2) , were elevated in the renal glomeruli of type 1 and type 2 diabetic patients who were protected from DN. TEPP46, a small-molecule which activates PKM2 by inducing oligomerization, reversed glomerular pathology in diabetic mice. Here, mice with PKM2-specific overexpression in podocytes (PPKM2Tg) were generated to uncover its renal protective function as potential therapeutic target, which prevented elevated albumin-creatinine ratio (ACR) , mesangial expansion, basement membrane thickness and podocyte foot process effacement after 7-months of STZ-induced diabetes. Further, diabetes-induced impairment of glycolytic rate and mitochondrial function were normalized in diabetic PPKM2Tg glomeruli, in concordance with elevated Ppargc1a and Vegf expressions. Restored VEGF expression improved glomerular maximal mitochondrial function in diabetic PPKM2Tg and WT mice. Elevated VEGF levels were observed in the glomeruli of DN-protected patients with chronic type 1 diabetes, and clinically correlated with estimated GFR, but not glycemic control. Mechanistically, the preservations of mitochondrial function and VEGF expression were dependent on tetrameric structure and enzymatic activities of PKM2 in podocyte. Thus, these findings show that PKM2 activation in the podocyte can regulate mitochondrial metabolism of the entire glomeruli and prevent mitochondrial dysfunction induced by chronic diabetes and even reverse metabolic memory. PKM2 structures and enzymatic activities are necessary to mediate glomerular metabolism against toxicity of hyperglycemia via paracrine factors such as VEGF. Thus, PKM2 activation in podocyte is a potential therapeutic target to protect against DN. Disclosure J.Fu: None. T.Shinjo: None. Q.Li: None. K.Park: None. M.Yu: None. H.Yokomizo: None. Q.Huang: None. I.Wu: None. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc.

Cognitive profile of people with mild behavioral impairment in Brain Health Registry participants.

Dementia assessment includes cognitive and behavioral testing with informant verification. Conventional testing is resource-intensive, with uneven access. Online unsupervised assessments could reduce barriers to risk assessment. The aim of this study was to assess the relationship between informant-rated behavioral changes and participant-completed neuropsychological test performance in older adults, both measured remotely via an online unsupervised platform, the Brain Health Registry (BHR). Observational cohort study. Community-dwelling older adults participating in the online BHR. Informant reports were obtained using the BHR Study Partner Portal. The final sample included 499 participant-informant dyads. Participants completed online unsupervised neuropsychological assessment including Forward Memory Span, Reverse Memory Span, Trail Making B, and Go/No-Go tests. Informants completed the Mild Behavioral Impairment Checklist (MBI-C) via the BHR Study Partner portal. Cognitive performance was evaluated in MBI+/- individuals, as was the association between cognitive scores and MBI symptom severity. Mean age of the 499 participants was 67, of which 308/499 were females (61%). MBI + status was associated with significantly lower memory and executive function test scores, measured using Forward and Reverse Memory Span, Trail Making Errors and Trail Making Speed. Further, significant associations were found between poorer objectively measured cognitive performance, in the domains of memory and executive function, and MBI symptom severity. These findings support the feasibility of remote, informant-reported behavioral assessment utilizing the MBI-C, supporting its validity by demonstrating a relationship to online unsupervised neuropsychological test performance, using a previously validated platform capable of assessing early dementia risk markers.

Exercise and Syzygium aromaticum reverse memory deficits, apoptosis and mitochondrial dysfunction of the hippocampus in Alzheimer's disease

Ethnopharmacological relevanceAlzheimer's disease (AD), the most common disease in the brain, is associated with cognitive and mitochondrial dysfunction. Emerging evidence suggests that endurance training and Syzygium aromaticum (L.) Merrill and Perry (Myrtaceae) (commonly referred to as clove) are effective interventions to maintain oxidative balance and improve cognitive function. Aim of the studyThe present study aimed to investigate the effect of endurance training and clove oil affect spatial memory, apoptosis, mitochondrial homeostasis, and cognitive function in Alzheimer's rats. Materials and methods81 rats were randomly assigned to 9 groups: Healthy (H), sham (sh), Healthy-exercise (HE), Healthy-clove (HC), Healthy-exercise-clove (HEC), Alzheimer's (A), Alzheimer's-exercise (AE), Alzheimer's-clove (AC), and Alzheimer's-exercise-clove (AEC). Alzheimer's induction was induced by the injection of 1–42 amyloid into the CA1 region of the hippocampus. The exercise training protocol was performed for 3 weeks, every day for 30 min in swimming training, and clove oil supplementation (0.1 mg/kg) was gavaged daily for 3 weeks in the supplement rat. Shuttle box test was used to measure spatial memory after the last training session, and to determine the mRNAs and protein levels and apoptosis, Real-Time PCR, immunofluorescent, and tunnel methods were used, respectively. ResultsAlzheimer's caused a significant decrease in the PRDX6 and GCN5L1 mRNAs and protein levels and a significant increase in apoptosis in the hippocampus of the Alzheimer's group compared to the control group (P = 0.001). Alzheimer's also reduced the time delay in entering the dark environment and increased the time spent in the dark environment (P = 0.001). Following endurance training and consumption of clove oil, spatial memory (P = 0.001), apoptosis (P = 0.001) and mRNAs and protein levels of PRDX6 (P = 0.001) and GCN5L1 (P = 0.017), were recovered in AE, AC and AEC groups, as compared with A group. ConclusionSwimming training and consumption of clove can possibly be considered as an effective intervention to maintain oxidative balance and improve mitochondrial homeostasis in Alzheimer's disease.

Near-infrared target enhanced peripheral clearance of amyloid-β in Alzheimer's disease model

Clearance of peripheral amyloid-β (Aβ) has been demonstrated particularly promising for overcoming the blood-brain barrier (BBB) hurdle to remove brain-derived Aβ associated with Alzheimer's disease (AD). However, currently used therapeutic agents targeting peripheral Aβ cannot simultaneously achieve plasma Aβ enrichment and enhanced clearance, which may result in poor bioavailability and rather low efficacy. Moreover, most of therapeutic agents usually promote the unfavorable aggregation of Aβ. Herein, we construct a near-infrared (NIR) regulated surface-transformable and target peptide-guided upconversion platform (UCNP/ONA-P/K), serving as a safe and effective way for Aβ clearance. Taking advantage of extended blood circulation, high selectivity toward Aβ, and surface-transformable property, such UCNP/ONA-P/K can address the challenges of peripheral Aβ clearance by a combination of enhancing the enrichment of plasma Aβ, preventing the unfavorable aggregation of Aβ and simultaneously facilitating the hepatic clearance of the captured Aβ. After verified by a series of systematic toxicity evaluation, cell uptake, deep tissue penetration, and hemolytic experiments, in vivo studies demonstrate that UCNP/ONA-P/K can efficiently decrease brain Aβ burden and reverse memory deficits in 3xTg-AD mice. Overall, this NIR multi-functional design provides a new biocompatible and efficient way for Aβ removal, which will promote the application of peripheral clearance of Aβ for AD treatment.