Background and objectives Stadice® is a proprietary herbal ingredient preparation standardized to mangiferin, developed to support cognitive wellness in healthy adults. Mangifera indica extract and its active constituent, mangiferin were known for its positive cognitive health benefits at experimental levels. This was an attempt to evaluate the clinical efficacy and safety of Stadice® on healthy subjects. Materials and methods A randomized, double-blind, placebo-controlled clinical study was designed to study the efficacy and safety of Stadice®. Sixty healthy subjects who were regularly playing virtual/mobile/computer/laptop games online or offline were asked to consume a capsule containing 300 mg of Stadice® or placebo per day for seven days. Cognitive ability tests, that were part of the NIMHANS Neuropsychological Battery and Auditory verbal learning tests were used to assess the cognitive health effects. Psychological stress response, anxiety, mood, subjective working memory, and cortisol levels were also assessed. All assessments were carried out at the baseline and at the end of the study. Results Stadice® was found to significantly improve mental speed, attention, working memory, response inhibition, and verbal learning and memory as evidenced by the results of the multiple cognitive ability tests. Additionally, Stadice ® showed beneficial responses in managing psychological stress in terms of handling nervousness, irritability, or mood swings. No safety concerns were found in the laboratory safety test parameters as they were within the normal physiological range and no adverse events were reported in this study. Conclusion The proprietary Mangifera indica extract (Stadice®) holds promise for enhancing cognitive abilities in healthy adults, particularly those engaged in esports. Improvements in learning, memory, mental speed, attention, response inhibition, and working memory among participants supplemented with Stadice® were observed with a good safety profile. Further exploration is warranted to ascertain its broader applicability as well as to elucidate the possible mechanisms.

Rosemary (Rosmarinus officinalis L.) is a rich source of dietary bioactive compounds such as rosmarinic acid and carnosol with a large repertoire of pharmacological properties, including anti-inflammatory and neuroprotective activities. In the present study, we investigated rosemary as a potential new therapeutic agent for cognitive function and other symptoms of aging. In this present study, we have aimed to investigate the effects of oral administration of rosemary extract (RME) on learning and memory in the context of other biomarkers-related cognitive function and neurotransmitter levels in senescent accelerated prone 8 (SAMP8) mouse, a model of accelerating aging and Alzheimer\'s disease. The Morris water maze (MWM) test showed improved spatial learning and memory behavior in RME treated SAMP8 mouse. Moreover, RME decreased Aβ42 and inflammatory cytokine levels and increased BDNF, Sirt1, and neurotransmitter levels in SAMP8 mouse. Whole-genome microarray analysis revealed that RME significantly increased gene expression related to oligodendrocyte differentiation, myelination, and ATP production in the hippocampus and decreased gene expression related to stress, neuroinflammation, and apoptosis. Also, in the SAMP8 hippocampus, RME significantly increased Olig1 and Olig2 expression. Altogether, our study is the first to report improvement of spatial learning and memory of RME, modulation of genes important for oligodendrogenesis, and Anti-neuroinflammatory effect by suppressing Aβ42 levels in mouse brain and thus highlights the prospects of RME in the treatment of cognitive dysfunction and aging.

BACKGROUND: The impact of acrylamide (ACR) on learning and memory has garnered considerable attention. However, the targets and mechanisms are still unclear.
RESULTS: Elongation factor 2 (eEF2) was significantly upregulated in the results of serum proteomics. Results from in vitro and in vivo experiments indicated a notable upregulation of Eukaryotic elongation factor 2 kinase (eEF2K), the sole kinase responsible for eEF2 phosphorylation, following exposure to ACR (P < 0.05). Subsequent in vitro experiments using eEF2K siRNA and in vivo experiments with eEF2K-knockout mice demonstrated significant improvements in abnormal indicators related to ACR-induced learning and memory deficits (P < 0.05). Proteomic analysis of the hippocampus revealed Lpcat1 as a crucial downstream protein regulated by eEF2K. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that eEF2K may play a role in the process of ACR-induced learning and memory impairment by affecting ether lipid metabolism.
CONCLUSIONS: In summary, eEF2K as a pivotal treatment target in the mechanisms underlying ACR-induced learning and memory impairment, and studies have shown that it provides robust evidence for potential clinical interventions targeting ACR-induced impairments.

Neurogenesis persists throughout adulthood in the hippocampus and contributes to specific cognitive functions. In Alzheimer\'s disease (AD), the hippocampus is affected by pathology and functional impairment early in the disease. Human AD patients have reduced adult hippocampal neurogenesis (AHN) levels compared to age-matched healthy controls. Similarly, rodent AD models show a decrease in AHN before the onset of the classical hallmarks of AD pathology. Conversely, enhancement of AHN can protect against AD pathology and ameliorate memory deficits in both rodents and humans. Therefore, impaired AHN may be a contributing factor of AD-associated cognitive decline, rather than an effect of it. In this review we outline the regulation and function of AHN in healthy individuals, and highlight the relationship between AHN dysfunction and cognitive impairments in AD. The existence of AHN in humans and its relevance in AD patients will also be discussed, with an outlook toward future research directions. HIGHLIGHTS: Adult hippocampal neurogenesis occurs in the brains of mammals including humans. Adult hippocampal neurogenesis is reduced in Alzheimer\'s disease in humans and animal models.

Netrin-G2 is a membrane-anchored protein and is known to play critical roles in neuronal circuit development and synaptic organization. In this study, we identify compound heterozygous mutations of c.547delC, p.(Arg183Alafs*186) and c.605G>A, p.(Trp202*) in NTNG2 causing a syndrome exhibiting developmental delay, intellectual disability, hypotonia, and facial dysmorphism. To elucidate the underlying cellular and molecular mechanisms, CRISPR-Cas9 technology is employed to generate a knock-in mouse model expressing the R183Afs and W202X mutations. We report that the Ntng2R183Afs/W202X mice exhibit hypotonia and impaired learning and memory. We find that levels of CaMKII and p-GluA1Ser831 are decreased and excitatory postsynaptic transmission and long-term potentiation are impaired. To increase the activity of CaMKII, the mutant mice have received intraperitoneal injections of DCP-LA, a CaMKII agonist, and show improved cognitive function. Together, our findings reveal molecular mechanisms of how NTNG2 deficiency leads to impairments of cognitive ability and synaptic plasticity.

BACKGROUND: We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer\'s disease (AD). However, the effects of CA140 on Aβ/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown.
METHODS: To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted.
RESULTS: In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aβ/tau fibrillation, Aβ plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100β and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling.
CONCLUSIONS: Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aβ/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.

Obesity is a significant health concern that is correlated with various adverse health outcomes. Diet-induced obesity (DIO) is associated with impaired cognitive function. Pharmacological treatments for obesity are limited and may have serious adverse effects. Zingiber officinale (ZO) has anti-inflammatory and antioxidant effects, in addition to metabolic effects. This study aimed to assess the effects of Zingiber officinale supplementation on cognitive function, anxiety levels, neurotrophin levels, and the inflammatory and oxidative status in the cortex following DIO in mice. Two-month-old male Swiss mice were fed DIO or standard chow for 4 months and subsequently subdivided into the following groups (n = 10 mice/group): (i) control - vehicle (CNT + vehicle); (ii) CNT supplemented with ZO (CNT + ZO); (iii) obese mice (DIO + vehicle); and (iv) obese mice supplemented with ZO (DIO + ZO) (n = 10). Zingiber officinale extract (400 mg/kg/day) was administered for 35 days via oral gavage. The DIO + vehicle group exhibited impaired recognition memory. The CNT + ZO group presented a greater number of crossings in the open field. No difference between the groups was observed in the plus maze test. DIO + vehicle increased the DCFH and carbonylation levels in the cortex. The DIO + vehicle group presented a reduction in catalase activity. The expression of inflammatory or neurotrophin markers in the cerebral cortex was not different. In conclusion, our findings indicate that supplementation with ZO reverses the cognitive impairment in DIO mice and enhances the antioxidant status of the cerebral cortex.

Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer\'s disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aβ plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aβ deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.

The primary purpose of present study was to explore the effects of arsenic exposure on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear transcription factor-κB (NF-κB) signaling pathway in the hippocampus of offspring mice at different developmental stages. Sodium arsenite (NaAsO2) at doses of 0, 15, 30 or 60 mg/L administered to female mice and their pups. The nuclear translocation levels of NF-κB were assessed by EMSA. Real-time RT-PCR was used to measure Akt, NF-κB and PI3K mRNA levels. Protein expressions of PI3K, p-Akt, inhibitor kappa B kinase (IKK), p-NF-κB, protein kinase A (PKA), inhibitor kappa B (IκB), and cAMP response element-binding protein (CREB) were measured by Western blot. Results disclosed that exposure to 60 mg/L NaAsO2 could suppress NF-κB levels of nuclear translocation of postnatal day (PND) 20 and PND 40 mice. Arsenic downregulated the transcriptional and translational levels of PI3K, Akt and NF-κB. Additionally, protein expressions of p-IKK, p-IκB, PKA and p-CREB also reduced. Taken together, results of present study indicated that arsenic could downregulate the PI3K/Akt/NF-κB signaling pathway, particularly on PND 40, which might be involved in the cognitive impairments.

OBJECTIVE: Subjective cognitive symptoms are commonly reported after mild traumatic brain injury (mTBI) but are often not associated with objective cognitive performance. This may be due to limitations in traditional cognitive performance measures, which may not be sensitive to subtle variations in cognition in post-acute mTBI. This study explored associations between objective and subjective cognition using computer-based tasks of increasing cognitive load, proposed to be more sensitive to subtle differences in performance.
METHODS: Individuals with mTBI (n = 68) and trauma controls (n = 40) were prospectively recruited and assessed approximately 8 weeks post-injury. Participants completed measures of subjective symptom reporting, objective cognitive performance (including two computer-based tasks of increasing cognitive load), and psychological distress.
RESULTS: There were no significant associations between subjective and objective cognition reporting in the mTBI group, both in bivariate correlations (|r| = 0.01-0.20, p > .05) and when controlling for psychological distress (|r| = 0.00-0.17, p > .05). A similar pattern of results was observed in trauma controls, suggesting that the limited relationships between objective and subjective cognition in mTBI may not be specific to this population.
CONCLUSIONS: Despite employing measures of cognitive performance proposed to be more sensitive than traditional tasks, no significant relationships were observed between objective and subjective cognition in post-acute mTBI, and estimated effect sizes were small to negligible. This provides further evidence that at a group level 8 weeks after mTBI subjective cognitive symptoms primarily reflect factors aside from objective cognition.