Alzheimer's Disease Cognitive Impairment Research Articles

Integrated cerebellar radiomic‐network model for predicting mild cognitive impairment in Alzheimer's disease

AbstractINTRODUCTIONPathological and neuroimaging alterations in the cerebellum of Alzheimer's disease (AD) patients have been documented. However, the role of cerebellum‐derived radiomic and structural connectome modeling in the prediction of AD progression remains unclear.METHODSRadiomic features were extracted from magnetic resonance imaging (MRI) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (n = 1319) and an in‐house dataset (n = 308). Integrated machine learning models were developed to predict the conversion risk of normal cognition (NC) to mild cognitive impairment (MCI) over a 6‐year follow‐up.RESULTSThe cerebellar models outperformed hippocampal models in distinguishing MCI from NC and in predicting transitions from NC to MCI across both cohorts. Key predictors included textural features in the right III and left I and II lobules, and network properties in Vermis I and II, which were associated with cognitive decline in AD.DISCUSSIONCerebellum‐derived radiomic‐network modeling shows promise as a tool for early identification and prediction of disease progression during the preclinical stage of AD.Highlights Altered cerebellar radiomic features and topological networks were identified in the subjects with mild cognitive impairment (MCI). The cerebellar radiomic‐network integrated models outperformed hippocampal models in distinguishing MCI from normal cognition. The cerebellar radiomic model effectively predicts MCI risk and can stratify individuals into distinct risk categories. Specific cerebellar radiomic features are associated with cognitive impairment across various stages of amyloid beta and tau pathology.

Elevated serum sodium is linked to increased amyloid-dependent tau pathology, neurodegeneration, and cognitive impairment in Alzheimer's disease.

Vascular dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). While sodium is essential for maintaining vascular function, its role in AD pathology remains unclear. We included 353 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), assessing serum sodium levels, cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, magnetic resonance imaging (MRI), and cognitive function. An independent sample (N = 471) with available CSF sodium-related proteins and AD biomarkers was also included. Associations between serum sodium levels and AD pathology, neurodegeneration, and cognition were evaluated using linear regression models. Spearman's correlation analyses assessed the relationships between CSF sodium-related proteins and AD biomarkers. Higher serum sodium levels were associated with increased AD pathology, reduced hippocampal volume, and greater cognitive decline (all p < 0.05). The relationship between serum sodium and amyloid PET was evident in several AD-susceptible brain regions, including the neocortex and limbic system. Individuals with high serum sodium exhibited higher tau pathology, lower hippocampal volume, and more severe cognitive decline per unit increase in amyloid PET compared to those with low serum sodium (all p < 0.05). Among the 14 CSF sodium-related proteins, which were inter-correlated, six were significantly correlated with CSF AD pathology and amyloid PET, while two were correlated with hippocampal volume and cognitive function, with sodium channel subunit beta-2 (SCN2B) and sodium channel subunit beta-3 (SCN3B) showing the strongest correlations. These findings underscore the crucial role of serum sodium in AD progression, highlighting a potential network of sodium dysregulation involved in AD pathology. Targeting sodium may offer a novel therapeutic approach to slowing AD progression, particularly by impeding the progression of amyloid-related downstream events.

Exploring the potential molecular targets of hydroxymethylbutyrate and glucosamine fortified whey protein drink to modulate sarcopenia and Alzheimer's disease by in silico and in vitro studies

Fortified foods have garnered significant attention as potential therapeutic strategies with less adverse effects and ready accessibility. However, precise formulation is required to optimize their beneficial effects. Our study aimed to unravel the mechanisms of a functional protein beverage, hydroxymethylbutyrate and glucosamine fortified whey protein drink (HG-WPD), as a possible intervention combatting sarcopenia and Alzheimer's disease (AD) by network pharmacology, molecular docking, and experimental assays. This study investigates the molecular pathways through which HG-WPD acts, by combining in silico and in vitro analyses. Our in silico study predicted the important target proteins, including acetylcholinesterase (AChE), matrix metalloproteinase 9 (MMP9), and angiotensin-converting enzyme (ACE), linked to both diseases. The molecular docking analysis showed that hydroxymethylbutyrate and glucosamine exhibited a notable binding affinity to these proteins, therefore suggesting their possible use as multi-target medicinal agents. In vitro studies on C2C12 myotubes showed that HG-WPD reduced dexamethasone-induced cell death highlighting its potential anti-sarcopenic actions. Furthermore, confirming their possible function in reducing cognitive impairment in AD, the antioxidant tests showed great activity of both substances. The results imply that HG-WPD is potentially effective for future therapeutic approaches as a functional food product with dual benefits in combatting sarcopenia and AD.

Is KIBRA polymorphism associated with memory performance and cognitive impairment in Alzheimer's disease?

Genetic variations in a common single nucleotide polymorphism in the ninth intron of the KIBRA gene have been linked to memory performance and risk of Alzheimer's disease (AD). We examined the risk of AD related to presence of KIBRA T allele (versus CC homozygote) and to memory performance. The role of established genetic risk factors APOE ε4 and BDNF Met was also considered. Participants were cognitively healthy individuals (n = 19), participants with amnestic mild cognitive impairment (aMCI) due to AD (n = 99) and AD dementia (n = 37) from the Czech Brain Aging Study. Binary and multinomial logistic regressions compared odds of belonging to a certain diagnostic category and multivariate linear regressions assessed associations with memory. KIBRA T allele was associated with increased AD dementia risk (odds ratio [OR] = 5.98, p = 0.012) compared to KIBRA CC genotype. In APOE ε4 negative individuals, KIBRA T allele was associated with a greater risk of both aMCI due to AD (OR = 6.68, p = 0.038) and AD dementia (OR = 15.75, p = 0.009). In BDNF Met positive individuals, the KIBRA T allele was associated with a greater risk of AD dementia (OR = 10.98, p = 0.050). In AD dementia, the association between KIBRA T allele and better memory performance approached significance (β = 0.42; p = 0.062). The link between possessing the KIBRA T allele and better memory reached statistical significance only among BDNF Met carriers (β = 1.21, p = 0.027). Findings suggest that KIBRA T allele may not fully protect against AD dementia but could potentially delay progression of post-diagnosis cognitive deficits.

Melatonin and Hydrogen Sulfide ameliorates cognitive impairments in Alzheimer's disease rat model exposed to chronic mild stress via attenuation of neuroinflamation and inhibition of oxidative stress: Potential role of BDNF

Melatonin and Hydrogen Sulfide ameliorates cognitive impairments in Alzheimer's disease rat model exposed to chronic mild stress via attenuation of neuroinflamation and inhibition of oxidative stress: Potential role of BDNF

Licochalcone A Ameliorates Cognitive Dysfunction in an Alzheimer's Disease Model by Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis.

Endoplasmic reticulum (ER) stress-induced neurodegeneration has been considered an underlying cause of Alzheimer disease (AD). Here, we investigated the beneficial effects of licochalcone A (Lico A), a valuable flavonoid of the root of the Glycyrrhiza species, against cognitive impairment in AD by regulating ER stress. The triple transgenic mouse AD models were used and were administrated 5 or 15mg/kg Lico A. Cognitive deficits, Aβ deposition, ER stress, and neuronal apoptosis were determined using Morris Water Maze test, probe trial, immunofluorescence staining, western blotting, and TUNEL staining. To investigate the mechanisms of how Lico A exerts anti-AD effects, primary hippocampal neurons were isolated from the AD model mice and treated with Lico A, salubrinal, an eIF2α phosphatase inhibitor, ML385, a Nrf2 inhibitor, or LY294002, an inhibitor of PI3K. Pharmacokinetics and toxicity of Lico A (15mg/kg) in AD mice were evaluated. We found that Lico A improved cognitive impairment, decreased Aβ plaques, inhibited ER stress, and reduced neuronal apoptosis in the hippocampus and cortex of AD mice. Treatment with Lico A in primary hippocampal neurons exerted the same effects as it did in vivo. Additionally, cotreatment with ML385 or LY294002 significantly impeded the effects of Lico A against ER stress. Moreover, 15mg/kg Lico A had a good bioavailability and low toxicity in AD mice. Our results demonstrated that Lico A ameliorates ER stress-induced neuronal apoptosis by inhibiting PERK/eIF2α/ATF4/CHOP signaling, suggesting the therapeutic potential of Lico A in AD treatment.

Ten-words recall test: an effective tool to differentiate mild cognitive impairment from subjective cognitive decline.

Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are stages 2 and 3, respectively, of the Alzheimer's continuum. The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog's) ten-words recall test is a validated method for the early detection of cognitive impairment in Alzheimer's disease. However, limited studies have investigated its ability to differentiate between SCD and MCI. 203 participants with SCD and 62 participants with MCI underwent multiple neuropsychological assessments. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Basic (MOCA-B) served as brief global cognition tests. A binary logistic regression model was used to analyze the potential factors affecting MCI. The accuracy of the ten-words recall test was assessed using the area under the receiver operating characteristic (ROC) and the area under the curve (AUC). The neuropsychological assessment revealed significant differences in the ten-words recall test scores between the SCD (median age 61 years; 70.44% female) and MCI (median age 64 years; 61.29% female) groups (p < 0.001), with the MCI group scoring the highest. Using a cut-off value of 3.15 for the ten-words recall test, sensitivity for distinguishing MCI from SCD reached 87%, while specificity stood at 61% (AUC 0.777, p < 0.001). DeLong's test indicated no statistically significant difference in the ten-words recall test's ability to distinguish between SCD and MCI compared to the total score of ADAS-Cog (AUC 0.833, p) and MMSE (AUC 0.784, p > 0.05). However, a significant difference was observed when compared to MoCA-B (AUC 0.973, p < 0.001). In the population with an education level of ≤ 9 years, the optimal cut-off value for the ten-words recall test was 3.15, yielding a sensitivity of 91% and a specificity of 45% (AUC = 0.674, p = 0.030). In the population with an education level > 9 years, the optimal cut-off value was 3.63, resulting in a sensitivity of 79% and a specificity of 71% (AUC = 0.785, p < 0.001). The ten-words recall test from the ADAS-cog may detect MCI early owing to its simplicity and quick administration. It is an effective and convenient tool for rapidly identifying mild cognitive impairment.

Co-activation of selective nicotinic acetylcholine receptor subtypes is required to reverse hippocampal network dysfunction and prevent fear memory loss in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia with no known cause and cure. Research suggests that a reduction of GABAergic inhibitory interneurons' activity in the hippocampus by beta-amyloid peptide (Aβ) is a crucial trigger for cognitive impairment in AD via hyperexcitability. Therefore, enhancing hippocampal inhibition is thought to be protective against AD. However, hippocampal inhibitory cells are highly diverse, and these distinct interneuron subtypes differentially regulate hippocampal inhibitory circuits and cognitive processes. Moreover, Aβ unlikely affects all subtypes of inhibitory interneurons in the hippocampus equally. Hence, identifying the affected interneuron subtypes in AD to enhance hippocampal inhibition optimally is conceptually and practically challenging. We have previously found that Aβ selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, α7- and α4β2-nAChRs, but not α3β4-nAChRs, and inhibits these two receptors in cultured hippocampal inhibitory interneurons to decrease their activity, leading to hyperexcitation and synaptic dysfunction in excitatory neurons. We have also revealed that co-activation of α7- and α4β2-nAChRs is required to reverse the Aβ-induced adverse effects in hippocampal excitatory neurons. Here, we discover that α7- and α4β2-nAChRs predominantly control the nicotinic cholinergic signaling and neuronal activity in hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively. Furthermore, we reveal that co-activation of these receptors is necessary to reverse hippocampal network dysfunction and fear memory loss in the amyloid pathology model mice. We thus suggest that co-activation of PV+ and SST+ cells is a novel strategy to reverse hippocampal dysfunction and cognitive decline in AD.

Impaired temporal coding associated with central auditory dysfunction and cognitive impairment in Alzheimer’s disease

Impaired temporal coding associated with central auditory dysfunction and cognitive impairment in Alzheimer’s disease

PFOS sub-chronic exposure selectively activates Aβ clearance pathway to improve the cognitive ability of AD mice

Perfluorooctane sulfonate (PFOS), an emerging persistent organic pollutant, has been controversial in its impact on cognitive functions. Our previous research has confirmed that the sub-chronic PFOS exposure leads to neuronal apoptosis in the cerebral cortex, impairing cognitive functions in normal mice. However, our current study presents a surprising finding: sub-chronic exposure to PFOS effectively reduces cognitive impairments in Alzheimer's disease (AD) mice and significantly retards the disease's progression. Our results indicate that PFOS exposure upregulates the expression level of insulin-degrading enzyme (IDE) in the prefrontal cortex (PFC) of AD mice, thereby selectively enhancing the amyloid-beta (Aβ) clearance pathway without affecting the Aβ production. Moreover, PFOS exposure inhibits microglial proliferation and reduces inflammatory cytokines levels in the PFC of AD mice, providing further supporting for the pivotal role of IDE in attenuating AD progression under PFOS exposure. Collectively, our study is the first to demonstrate that sub-chronic PFOS exposure can alleviates cognitive impairments in AD pathology, with the IDE-mediated Aβ clearance pathway potentially playing a critical role.

Avicularin inhibits ferroptosis and improves cognitive impairments in Alzheimer's disease by modulating the NOX4/Nrf2 axis

BackgroundAlzheimer's disease (AD) is a widespread neurodegenerative disorder for which effective therapies remain elusive, primarily due to the complexity of its underlying pathophysiology. In recent years, natural products have gained attention for their therapeutic potential in AD, owing to their multi-targeted actions and low toxicity profiles. Avicularin (Avi), a flavonoid derived from the peels of Zanthoxylum bungeanum Maxim., has shown promise as an anti-AD agent. However, the specific mechanisms by which Avi mitigates oxidative stress and inhibits ferroptosis in AD models remain insufficiently understood. Further investigation is required to elucidate its therapeutic potential in these pathways. PurposeTherefore, this study aims to elucidate the neuroprotective effects of Avi in AD by investigating its impact on the NOX4/Nrf2 signaling pathway, as well as its role in modulating oxidative stress and ferroptosis. MethodsIn this study, an in vitro H2O2-induced oxidative stress model in SH-SY5Y cells was utilized to evaluate the pharmacological efficacy and underlying mechanisms of Avi. Molecular docking, CETSA and BLI assays were conducted to identify potential molecular targets of Avi. Additionally, in vivo models, including scopolamine (SCOP)-induced and APP/PS1 transgenic mice, were employed to assess the cognitive effects of Avi and further explore its associated molecular mechanisms. ResultsOur study demonstrates that Avi effectively attenuates H2O2-induced toxicity in SH-SY5Y cells by reducing apoptosis and enhancing cellular antioxidant defenses. This neuroprotective effect is mediated through the inhibition of NOX4 and the promotion of Nrf2 nuclear translocation. Furthermore, Avi improves cognitive function and mitigates ferroptosis in both SCOP-induced and APP/PS1 transgenic mouse models of AD. ConclusionAvi emerges as an effective neuroprotective agent against AD, offering a promising therapeutic approach by targeting the NOX4/Nrf2 signaling axis to alleviate oxidative stress and ferroptosis.

Chronic stress induces insulin resistance and enhances cognitive impairment in AD

BackgroundChronic stress can induce the cognitive impairment, and even promote the occurrence and development of Alzheimer's disease (AD). Evidence has suggested that chronic stress impacts on glucose metabolism, and both of these have been implicated in AD. Here we focused on the effect of insulin resistance in glucose metabolism, and further evaluated the changes in cognition and pathology. MethodsMale 9-month-old wild-type and APP/PS1 mice were randomly divided into 4 groups. Mice in the chronic unpredictable mild stress (CUMS) groups were exposed for 4 weeks. Homeostatic Model Assessment (HOMA) was utilized to evaluate insulin sensitivity. A total of eighty-four genes related to the insulin signaling pathway were examined for rapid screening. Additionally, the phosphorylated protein expressions of insulin receptors (IR), IR substrate 1 (IRS1), c-Jun N-terminal kinase (JNK), and amyloid were detected in the hippocampus. Cognitive function was assessed through ethological methods. Cognitive function was assessed using both the Morris water maze (MWM) and the Passive avoidance test (PAT). ResultsFour weeks of CUMS exposure significantly increased the HOMA value, indicating reduced insulin sensitivity. The gene expressions of Insr and Lipe were downregulated. Additionally, the analysis revealed a significant interaction between the genotype (wild-type vs. APP/PS1) and CUMS treatment on the phosphorylated protein expressions of insulin receptor substrate 1 (IRS1). Specifically, CUMS exposure increased the inhibitory phosphorylation site (IRS1-pSer636) and decreased the excitatory phosphorylation site (IRS1-pTyr465) in the post-insulin receptor signaling pathway within the hippocampus of both wild-type and APP/PS1 mice. Moreover, CUMS exposure induced and exacerbated cognitive impairments in both wild-type and APP/PS1 mice, as assessed by the Morris water maze (MWM) and Passive avoidance test (PAT). However, there was no significant effect of CUMS on senile plaque deposition or levels of Aβ42 and Aβ40 in wild-type mice. ConclusionsChronic stress significantly affects hippocampal cognitive function through insulin resistance and exacerbates AD pathology. This study reveals the complex relationship between chronic stress, insulin resistance, and AD, providing new insights for developing interventions targeting chronic stress and insulin resistance.

A - 119 Cognitive Impairment in Alzheimer’s Disease: the Impacts on Reasoning and Decision-Making in Healthcare

Abstract Objective Alzheimer’s Disease (ad) is a progressive neurodegenerative disease characterized by the presence of amyloid plaques and neurofibrillary tangles. These brain changes negatively affect inter-neuron firing, leading to memory loss and slow cognitive decline. Older adults with ad experience deficits in activities of daily living and an increased need for supervision. This systematic review investigates the cognitive impairments seen in ad patients relative to normal aging, focusing on how the neuropathology of Alzheimer’s affects their reasoning and decision-making abilities in healthcare settings. Data Selection Data was gathered from PubMed, PsycINFO, and Google Scholar. Terms used in the literature review included cognitive impairment in ad, executive function in ad, Alzheimer’s and its impact in decision-making, decision-making and cognitive impairment, decision-making and the elderly, caregiver burden and burnout in ad, neuropsychology in ad, neuropsychological assessment in ad, neuropathology in ad. Data search was conducted from January 15–18 and March 3–4 of 2024. Examination of 45 studies were conducted. Data Synthesis Patients with ad demonstrate severe brain structure deterioration, leading to cognitive impairment that impacts reasoning and decision-making. Early diagnosis and neuropsychological assessments are crucial to establish a baseline and monitor changes in cognition. Appropriate care management is key to preserving patient self-determination in healthcare decision-making and reducing the burden on caregivers. Conclusions ad significantly deteriorates patients’ ability to reason and make informed decisions, necessitating early and precise interventions. Future research should investigate innovative diagnostic tools and intervention strategies to enhance decision-making capabilities, improve patient quality of life, and reduce caregiver burden.

A - 21 The Association between Tau Pathology and Cognitive Impairment in Alzheimer’s Disease in the Democratic Republic of Congo

Abstract Objective Previous studies in Western countries have shown that tau accumulation is more closely connected with cognitive decline in Alzheimer’s disease (ad). This association has not yet been investigated in the Sub-Saharan African countries/Democratic Republic of Congo (DRC). We investigated the association between phosphorylated tau (p-Tau) level and cognitive performance of older adults from the DRC. Method Blood and neuropsychological tests were collected on 80 Congolese older adults with suspected ad. Participants were classified according to the biomarkers of their ATN profiles with positive “A” values based on β-amyloid &amp;lt;0.061 and “T” values based on p-Tau 181 &amp;lt; 4.50, as well as APOEε4 using Simoa assays. An analysis of covariance examined the differences in memory performance for each pathological group, controlling for age, education, gender, and APOEε4 status. Results A-T- (n = 36) consisted of age (M = 71.3, SD = 7.44), gender (48.6% female), education level (M = 9.80, SD = 5.44), and APOEε4 (38.2%). A + T- (n = 29) consisted of age (M = 73.1, SD = 7.75), gender (62.1% female), education level (M = 7.21, SD = 5.92), and APOEε4 (41.4%). A + T+ (n = 15) consisted of age (M = 78.1, SD = 4.62), gender (60.0% female), education level (M = 6.60, SD = 3.46), and APOEε4 (93.3%). Overall, there were significant effects of memory performances on A-T- participants: verbal memory immediate (p = 0.0089), delayed (p = 0.00096), and recognition (p = 0.0104); and visual memory delayed (p = 0.00058) and recognition (p = 0.00039). Conclusion Reduced memory performance and p-Tau levels were associated in Congolese adults with and without ad. This study suggests abnormal tau accumulation underlies cognitive deficits in ad and could be used as an early marker of ad pathology for various populations in Sub-Saharan African countries.

A combination of Δ9-tetrahydrocannabinol and cannabidiol modulates glutamate dynamics in the hippocampus of an animal model of Alzheimer's disease

A combination of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) at non-psychoactive doses was previously demonstrated to reduce cognitive decline in APP/PS1 mice, an animal model of Alzheimer's disease (AD). However, the neurobiological substrates underlying these therapeutic properties of Δ9-THC and CBD are not fully understood. Considering that dysregulation of glutamatergic activity contributes to cognitive impairment in AD, the present study evaluates the hypothesis that the combination of these two natural cannabinoids might reverse the alterations in glutamate dynamics within the hippocampus of this animal model of AD. Interestingly, our findings reveal that chronic treatment with Δ9-THC and CBD, but not with any of them alone, reduces extracellular glutamate levels and the basal excitability of the hippocampus in APP/PS1 mice. These effects are not related to significant changes in the function and structure of glutamate synapses, as no relevant changes in synaptic plasticity, glutamate signaling or in the levels of key components of these synapses were observed in cannabinoid-treated mice. Our data instead indicate that these cannabinoid effects are associated with the control of glutamate uptake and/or to the regulation of the hippocampal network. Taken together, these results support the potential therapeutic properties of combining these natural cannabinoids against the excitotoxicity that occurs in AD brains.

Improvement of olfactory function in AD mice mediated by immune responses under 40 Hz light flickering

Background40 Hz light flickering has shown promise as a non-invasive therapeutic approach for alleviating both pathological features and cognitive impairments in Alzheimer’s disease (AD) model mice and AD patients. Additionally, vision may influence olfactory function through cross-modal sensory interactions. ObjectiveTo investigate the impact of 40 Hz light flickering on olfactory behavior in AD model mice and to explore the underlying mechanisms of this intervention. MethodsWe used immunofluorescence techniques to observe the activation of the olfactory bulb (OB) in C57BL/6J mice under 40 Hz light flickering. A buried food test was conducted to evaluate olfactory behavior in AD mice. Additionally, RNA sequencing technology was employed to detect transcriptional alterations in the OBs of AD mice following light stimulation. Results40 Hz light flickering was found to effectively activate the OB. This stimulation led to enhanced olfactory behavior and did not alter P-tau protein mRNA levels within the OBs of AD mice. RNA sequencing revealed significant transcriptional changes in the OBs under flickering, particularly related to immune responses. ConclusionVision can influence olfactory function through cross-modal sensory interactions in rodent models. 40 Hz light stimulation improved olfactory performance in AD mice. However, the improvement in olfaction in AD mice is not related to changes in P-tau mRNA levels. Instead, it may be associated with an altered immune response, providing a scientific basis for the clinical treatment of olfactory disorders in Alzheimer’s disease.

Quercetagetin 3,7 dimethyl ether polymorphs as multi-targeted anti-amyloid agents: Target to cognitive impairment in Alzheimer's disease

The extraction of biologically active natural products from plants and the assessment of their medicinal properties play a crucial role in drug development. Taking that into consideration, the current research work was designed. Bioassay-guided isolation from Parthenium hysterophorus led to the isolation of two antioxidant compounds: polymorphs A (1) and B (2) of Quercetagetin 3,7-dimethyl ether which demonstrated IC50 values 13.00 ± 0.63 μM and 16.56 ± 0.82 μM, respectively in the DPPH assay. These polymorphs were further evaluated for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. In silico studies, including molecular docking, and molecular dynamic simulations were conducted using β-secretase, γ-secretase, AChE, and BChE enzymes. Interestingly, compound 1 demonstrated excellent antioxidant activity and showed the better binding affinities -9.0 kcal/mol (BChE), −8.5 kcal/mol (β-secretase), -8.2 kcal/mol (γ-secretase) and -7.7 kcal/mol (AChE) as compared to compound 2. Due to these promising results, compound 1 was selected for molecular dynamic simulations to further evaluate the stability and flexibility of its complexes. Overall, both in silico and in vitro results confirmed that compound 1 and compound 2 exhibit distinct behavior, making them promising candidates as antioxidants and inhibitors of AChE, BChE, and secretases, potentially targeting cognitive impairment in Alzheimer's disease (AD).

The relationship between adult hippocampal neurogenesis and cognitive impairment in Alzheimer's disease.

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.

Carotenoid Supplementation for Alleviating the Symptoms of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by, among other things, dementia and a decline in cognitive performance. In AD, dementia has neurodegenerative features and starts with mild cognitive impairment (MCI). Research indicates that apoptosis and neuronal loss occur in AD, in which oxidative stress plays an important role. Therefore, reducing oxidative stress with antioxidants is a natural strategy to prevent and slow down the progression of AD. Carotenoids are natural pigments commonly found in fruits and vegetables. They include lipophilic carotenes, such as lycopene, α- and β-carotenes, and more polar xanthophylls, for example, lutein, zeaxanthin, canthaxanthin, and β-cryptoxanthin. Carotenoids can cross the blood-brain barrier (BBB) and scavenge free radicals, especially singlet oxygen, which helps prevent the peroxidation of lipids abundant in the brain. As a result, carotenoids have neuroprotective potential. Numerous in vivo and in vitro studies, as well as randomized controlled trials, have mostly confirmed that carotenoids can help prevent neurodegeneration and alleviate cognitive impairment in AD. While carotenoids have not been officially approved as an AD therapy, they are indicated in the diet recommended for AD, including the consumption of products rich in carotenoids. This review summarizes the latest research findings supporting the potential use of carotenoids in preventing and alleviating AD symptoms. A literature review suggests that a diet rich in carotenoids should be promoted to avoid cognitive decline in AD. One of the goals of the food industry should be to encourage the enrichment of food products with functional substances, such as carotenoids, which may reduce the risk of neurodegenerative diseases.

Maresin1 restrains chronic inflammation and Aβ production to ameliorate Alzheimer's disease via modulating ADAM10/17 and its associated neuroprotective signal pathways: A pilot study

Chronic inflammation is an important pathogenetic factor that leads to the progression of Alzheimer's disease (AD), and specialized pro-resolving lipid mediators (SPMs) play critical role in regulating inflammatory responses during AD pathogenesis. Maresin1 (MaR1) is the latest discovered SPMs, and it is found that MaR1 improves AD cognitive impairment by regulating neurotrophic pathways to protect AD synapses and reduce Aβ production, which made MaR1 as candidate agent for AD treatment. Unfortunately, the underlying mechanisms are still largely known. In this study, the AD mice and cellular models were subjected to MaR1 treatment, and we found that MaR1 reduced Aβ production to ameliorate AD-related symptoms and increased the expression levels of ADAM10/17, sAPPα and sAPPβ to exert its anti-inflammatory role. In addition, as it was determined by Western Blot analysis, we observed that MaR1 could affected the neuroprotective signal pathways. Specifically, MaR1 downregulated p57NTR and upregulated TrkA to activate the p75NTR/TrkA signal pathway, and it could increase the expression levels of p-PI3K and p-Akt, and downregulated p-mTOR to activate the PI3K/AKT/ERK/mTOR pathway. Finally, we verified the role of ADAM10/17 in regulating AD progression, and we found that silencing of ADAM10/17 inactivated the above neuroprotective signal pathways to aggravate AD pathogenesis. In conclusion, MaR1 is verified as potential therapeutic agent for AD by eliminating Aβ production, upregulating ADAM10/17, sAPPα and sAPPβ, and activating the neuroprotective p75NTR/TrkA pathway and the PI3K/AKT/ERK/mTOR pathway.