Progressive Memory Impairment Research Articles

Metabolic profiling of Vitex Pubescens Vahl bark via UPLC-ESI-QTOF/MS/MS analysis and evaluation of its antioxidant and acetylcholinesterase inhibitory activities

BackgroundAlzheimer’s disease is a neurodegenerative age-related disease that primarily affects the elderly population leading to progressive memory impairments and neural deficits. It is counted as a major cause of geriatric dependency and disability. The pathogenesis of Alzheimer’s disease incidence is complex and involves various hypotheses, including the cholinergic hypothesis, deposition of β-amyloid plaques, neuroinflammation, oxidative stress, and apoptosis. Conventional treatments such as donepezil aim to delay the symptoms but do not affect the progression of the disease and may cause serious side effects like hepatoxicity. The use of natural candidates for Alzheimer’s disease treatment has drawn the attention of many researchers as it offers a multitargeted approach.MethodsThis current study investigates the metabolic profiles of total defatted methanolic extract of Vitex pubescens bark and its polar fractions, viz. ethyl acetate and n-butanol, using ultra-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight tandem mass spectrometry(UPLC-ESI-QTOF/MS/MS) technique as well as evaluate the antioxidant using free radical scavenging assays, viz. DPPH and ABTS assays and in-vitro acetylcholinesterase inhibitory activities using Ellman’s microplate assay.ResultsMetabolic profiling revealed a total of 71, 43, and 55 metabolites tentatively identified in the defatted methanolic extract, ethyl acetate, and n-butanol fractions, respectively. Phenolic acids were the most abundant class, viz. benzoic acids, and acyl quinic acid derivatives followed by flavonoids exemplified mainly by luteolin-C-glycosides and apigenin-C-glycosides. Quantification of the total phenolic and flavonoid contents in the total defatted methanolic extract confirmed its enrichment with phenolics and flavonoids equivalent to 138.61 ± 9.39 µg gallic acid/mg extract and 119.63 ± 4.62 µg rutin/mg extract, respectively. Moreover, the total defatted methanolic extract exhibited promising antioxidant activity confirmed through DPPH and ABTS assays with a 50% inhibitory concentration (IC50) value equivalent to 52.79 ± 2.16 µg/mL and 10.02 ± µg/mL, respectively. The inhibitory activity of acetylcholine esterase (AchE) was assessed using in-vitro Ellman’s colorimetric assay, the total defatted methanolic extract, ethyl acetate, and n-butanol fractions exhibited IC50 values of 52.9, 15.1 and 108.8 µg/mL that they proved the significant inhibition of AchE activity.ConclusionThe results obtained herein unraveled the potential use of the total methanolic extract of Vitex pubescens bark and its polar fractions as natural candidates for controlling Alzheimer’s disease progression.

The beneficial effect of fluoxetine on behavioral and cognitive changes in chronic experimental Chagas disease unveils the role of serotonin fueling astrocyte infection by Trypanosoma cruzi.

In Chagas disease (CD), a neglected tropical disease caused by the parasite Trypanosoma cruzi, the development of mental disorders such as anxiety, depression, and memory loss may be underpinned by social, psychological, and biological stressors. Here, we investigated biological factors underlying behavioral changes in a preclinical model of CD. In T. cruzi-infected C57BL/6 mice, a kinetic study (5 to 150 days postinfection, dpi) using standardized methods revealed a sequential onset of behavioral changes: reduced innate compulsive behavior, followed by anxiety and depressive-like behavior, ending with progressive memory impairments. Hence, T. cruzi-infected mice were treated (120 to 150 dpi) with 10 mg/Kg/day of the selective serotonin reuptake inhibitor fluoxetine (Fx), an antidepressant that favors neuroplasticity. Fx therapy reversed the innate compulsive behavior loss, anxiety, and depressive-like behavior while preventing or reversing memory deficits. Biochemical, histological, and parasitological analyses of the brain tissue showed increased levels of the neurotransmitters GABA/glutamate and lipid peroxidation products and decreased expression of brain-derived neurotrophic factor in the absence of neuroinflammation at 150 dpi. Fx therapy ameliorated the neurochemical changes and reduced parasite load in the brain tissue. Next, using the human U-87 MG astroglioma cell line, we found no direct effect of Fx on parasite load. Crucially, serotonin/5-HT (Ser/5-HT) promoted parasite uptake, an effect increased by prior stimulation with IFNγ and TNF but abrogated by Fx. Also, Fx blocked the cytokine-driven Ser/5-HT-promoted increase of nitric oxide and glutamate levels in infected cells. We bring the first evidence of a sequential onset of behavioral changes in T. cruzi-infected mice. Fx therapy improves behavioral and biological changes and parasite control in the brain tissue. Moreover, in the central nervous system, cytokine-driven Ser/5-HT consumption may favor parasite persistence, disrupting neurotransmitter balance and promoting a neurotoxic environment likely contributing to behavioral and cognitive disorders.

Cognitive disorders in Parkinson's disease

Movement disorders undoubtedly form the core of the Parkinson's disease (PD) clinical picture. However, several other clinical manifestations can significantly complicate the course of the disease. These are the so-called non-motor symptoms, which include emotional, cognitive, autonomic, and sensory disorders, as well as psychotic [1, 2, 3]. According to DSM-IV criteria (American Psychiatric Association, 1994), dementia in PD can be presented as a progressive memory impairment syndrome in the absence of aphasia, apraxia, or agnosia. Keywords: Parkinson's disease; cognitive disorders; dementia; Alzheimer's disease; levodopa; acetylcholinesterase inhibitors

Euonymus alatus Leaf Extract Attenuates Effects of Aging on Oxidative Stress, Neuroinflammation, and Cognitive Impairment.

Our study aimed to explore the impact and mechanism of Euonymus alatus leaf extract on age-dependent oxidative stress, neuroinflammation, and progressive memory impairments in aged mice. Twenty-four-month-old mice received EA-L3 (300 mg/kg/day) or the reference drug, donepezil (DPZ, 5 mg/kg/day), for 6 weeks, and learning and memory functions were detected using the Passive Avoidance Test (PAT). As expected, cognitive function deficits were detected in aged mice compared with young mice, and these deficits were significantly mitigated by dietary treatments with EA-L3. In parallel, it upregulated the brain-derived neurotrophic factor (BDNF) and subsequently activated the extracellular-signal-regulated kinase (ERK)/cAMP response element-binding (CREB) signaling in the mouse hippocampus and scopolamine-induced B35 and SH-SY5Y neuroblastoma cells. EA-L3 showed strong anti-inflammatory effects with decreased NF-κBp65, cyclooxygenase 2 (COX-2), and tumor necrosis factor alpha (TNF-α), increased interleukin (IL)-10, and doublecortin (DCX) protein expression in the hippocampus of aged mice. Similar results were also confirmed in LPS-induced BV-2 microglia and neuroblastoma cells upon treatment with EA-L3 extract. In addition, EA-L3 notably dose-dependently decreased ROS in BV2 cells after exposure to LPS. Taken together, EA-L3 might be used as a dietary supplement to alleviate oxidative stress, the deterioration of hippocampal-based memory tasks, and neuroinflammation in elderly people.

Early Detection of Alzheimers Disease through Deep Learning in MRI Scans

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and memory impairment, leading to dementia and irreversible decline in cognitive abilities. This disease causes the person to suffer from memory loss, unusual behaviour, and language problems. The initial symptoms, such as episodic memory impairment and the navigational problem of the patient, are typical variants. In the proposed system we are using The Deep Learning Models as Modified CNN along with MobileNet, and VGG16 algorithms and classify the images as either Mild Demented or Moderate Demented or Non-Demented or Very Mild Demented. In this study we are using Augmented ADNI dataset which consists of 40000 images. This can be utilized in the future to classify the types of different classifications easily which is easy to find out the infections in initial stages and can be cured in the initial stages only.

Терапия болезни Альцгеймера на основе стволовых клеток

Alzheimer’s disease is a neurodegenerative disease characterized by extracellular accumulation of β-amyloid and intracellular aggregation of hyperphosphorylated tau into neurofibrillary tangles in the brain. It leads to progressive memory impairment and loss of daily living skills. Currently, there is no effective treatment for this disease, but the potential of stem cells for the therapy of neurodegenerative pathologies, inclu­ding Alzheimer’s disease, is being actively explored. Stem cell-secreted growth factors, extracellular vesicles can attenuate neuroinflammation and slow down cognitive deterioration during disease progression. This review highlights progress in preclinical studies using mouse models of different stem cell types as treatment stra­tegies for Alzheimer’s disease and provides insights into their translational applications. The article reviews the benefits, therapeutic effects and prospects of stem cells and their differentiating descendants, and provides current information on the mechanisms by which different types of stem and pluripotent cells are involved endogenous neurogenesis in Alzheimer’s disease. The data presented in this review contain information on cell therapy methods, both those already used in clinical practice and those being studied in various models, including transgenic mice. In the future, effective methods of obtaining and delivering of stem cells and their pro­ducts to achieve significant clinical results in patients with Alzheimer’s disease will be developed.

Probable Novel APP Met671Leu Mutation in a Chinese Han Family with Early-Onset Alzheimer's Disease.

Familial Alzheimer's disease (AD) is a rare disease caused by autosomal-dominant mutations. APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) are the most common genes cause dominant inherited AD. This study aimed to demonstrate a Chinese early-onset AD pedigree presenting as progressive memory impairment, apraxia, visual-spatial disorders, psychobehavioral disorders, and personality changes with a novel APP gene mutation. The family contains four patients, three carries and three normal family members. The proband underwent brain magnetic resonance imaging (MRI), 18F-fludeoxyglucose positron emission tomography (18F-FDG-PET), cerebrospinal fluid amyloid detection, 18F-florbetapir (AV-45) Positron Emission Computed Tomography (PET) imaging, whole-exome sequencing and Sanger sequencing. Brain MRI images showed brain atrophy, especially in the entorhinal cortex, temporal hippocampus, and lateral ventricle dilation. The FDG-PET showed hypometabolism in the frontotemporal, parietal, and hippocampal regions. 18F-florbetapir (AV-45) PET imaging showed cerebral cortex Aβ protein deposition. The cerebrospinal fluid amyloid protein test showed Aβ42/Aβ40 ratio decreases, pathological phosphor-tau level increases. Whole-exome sequencing detected a new missense mutation of codon 671 (M671L), which was a heterozygous A to T point mutation at position 2011 (c.2011A > T) in exon 16 of the amyloid precursor protein, resulting in the replacement of methionine to Leucine. The co-separation analysis was validated in this family. The mutation was found in 3 patients, 3 clinical normal members in the family, but not in the other 3 unaffected family members, 100 unrelated normal subjects, or 100 sporadic patients with AD. This mutation was probably pathogenic and novel in a Chinese Han family with early-onset AD.

Screening Techniques for Drug Discovery in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive and irreversible impairment of memory and other cognitive functions of the aging brain. Pathways such as amyloid beta neurotoxicity, tau pathogenesis and neuroinflammatory have been used to understand AD, despite not knowing the definite molecular mechanism which causes this progressive disease. This review attempts to summarize the small molecules that target these pathways using various techniques involving high-throughput screening, molecular modeling, custom bioassays, and spectroscopic detection tools. Novel and evolving screening methods developed to advance drug discovery initiatives in AD research are also highlighted.

HDAC9-mediated calmodulin deacetylation induces memory impairment in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. AD pathology involves protein acetylation. Previous studies have mainly focused on histone acetylation in AD, however, the roles of nonhistone acetylation in AD are less explored. The protein acetylation and expression levels were detected by western blotting and co-immunoprecipitation. The stoichiometry of acetylation was measured by home-made and site-specific antibodies against acetylated-CaM (Ac-CaM) at K22, K95, and K116. Hippocampus-dependent learning and memory were evaluated by using the Morris water maze, novel object recognition, and contextual fear conditioning tests. We showed that calmodulin (CaM) acetylation is reduced in plasma of AD patients and mice. CaM acetylation and its target Ca2+ /CaM-dependent kinase II α (CaMKIIα) activity were severely impaired in AD mouse brain. The stoichiometry showed that Ac-K22, K95-CaM acetylation were decreased in AD patients and mice. Moreover, we screened and identified that lysine deacetylase 9 (HDAC9) was the main deacetylase for CaM. In addition, HDAC9 inhibition increased CaM acetylation and CaMKIIα activity, and hippocampus-dependent memory in AD mice. HDAC9-mediated CaM deacetylation induces memory impairment in AD, HDAC9, or CaM acetylation may become potential therapeutic targets for AD.

Alzheimer’s Disease and Language: Development and Prospects

Alzheimer’s disease is a degenerative disease of the central nervous system characterized by progressive cognitive impairment and memory impairment. With search keywords set as “Alzheimer’s (disease)” and “language” and the publication date set from January 1, 2020 to October 30, 2022, we retrieved 61 pieces of Chinese literature from CNKI and 176 English results from the Web of Science Core Collection. Data were screened manually and processed with CiteSpace 6.1.R3 and biblioshiny. This study tries to map out the developments of research on language related to Alzheimer’s disease both in the Chinese science circle and the international academic circle during the recent two decades (2000-2022). Investigations are also conducted to identify possibilities and opportunities for research fronts. Current studies on the association between Alzheimer’s disease and language are characterized by task singularity, subject specificality, institution pluralism, and treatment locality. Future studies are suggested to incorporate neuro-scanning technologies to obtain a clearer message of the neural mechanism. Lifelong bilinguals who use language as a profession such as translators and interpreters are also possible subject groups for future investigations to grasp a both general and specific picture of the association between Alzheimer’s disease and language.To overcome our limitations, it is crucial to gather more scientific findings using non-destructive and highly sensitive technologies to understand language impairments in Alzheimer's disease more comprehensively.

Antioxidant and anti-Alzheimer's potential of Tetragonisca angustula (Jataí) stingless bee pollen

Alzheimer's disease (AD) is considered the leading cause of dementia in the elderly worldwide. It results in progressive memory loss and impairment of cognitive and motor skills, leading to a high degree of disability and dependence. The development of AD is associated with the accumulation of senile plaques in the brain, caused by the amyloidogenic pathway of the disease. Several genetic and biochemical events are linked to AD development, with oxidative stress being one of them. Due to the scarcity of drugs aimed at treating AD, antioxidant compounds are increasingly studied as therapeutic targets for the disease. In this study, we investigate the antioxidant and anti-Alzheimer potential of the Tetragonisca angustula (Jataí) pollen extract in a Drosophila melanogaster Alzheimer's model. For this purpose, we utilized a D. melanogaster AD-like model, which expresses genes related to the amyloidogenic pathway of Alzheimer's disease. We explored the floral origin of the collected pollen, conducted phytochemical prospecting, and evaluated its antioxidant capacity in vitro. In vivo experiments involved assessing the survival and climbing ability of the D. melanogaster AD-like model with various concentrations of the pollen extract. Our findings revealed that the pollen extract of Tetragonisca angustula exhibits a significant antioxidant response and high concentrations of important phytochemicals, such as flavonoids and polyphenols. Furthermore, it enhanced the survival rate of D. melanogaster, and across all concentrations tested, it improved the climbing ability of the flies after 15 days of treatment with methanolic pollen extract. Additionally, the pollen extract reduced the neurodegeneration index in histopathological analysis. Thus, our study demonstrates the potential of Tetragonisca angustula pollen as an important subject for further investigation, aiming to isolate molecules that could potentially serve as therapeutic targets for Alzheimer's disease.

Research and progress of focused ultrasound in the treatment of Alzheimer's disease.

Alzheimer's disease is one of the most common degenerative diseases of the central nervous system, with progressive cognitive and memory impairment and decreased ability of daily life as the cardinal symptoms, influencing the life quality of patients severely. There are currently approximately 46 million people living with Alzheimer's disease worldwide, and the number is expected to triple by 2050, which will pose a huge challenge for healthcare. At present, the Food and Drug Administration of the United States has approved five main drugs for the clinical treatment of Alzheimer's disease, which are cholinesterase inhibitors tacrine, galantamine, capalatine and donepezil, and N-methyl-d-aspartate receptor antagonist memantine, although these drugs have shown good efficacy in clinical trials, the actual clinical effect is less effective due to the existence of blood brain barrier. With the continuous development of ultrasound technology in recent years, focused ultrasound, as a non-invasive treatment technique, may target ultrasound energy to the deep brain for treatment without damaging the surrounding tissue. For the past few years, some studies could use focused ultrasound combined with microvesicles to induce blood brain barrier opening and targeted drug delivery to treat Alzheimer's disease, providing new opportunities for the treatment of Alzheimer's disease. This article reviews the application research and progress of focused ultrasound in the treatment of Alzheimer's disease, in order to provide new directions and ideas for the treatment of Alzheimer's disease.

Monosynaptic Rabies Viral Tracing Reveals Subiculum Circuit Connectivity Alterations in Alzheimer's Disease

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly and causes progressive memory and behavioral impairment. Examining the changes in neural circuitry using AD model mice is an emerging strategy for a better understanding of AD neural mechanisms toward discovering new therapeutic targets. Our recent work indicates the disruption of long-range and local neural circuit connections in the hippocampus using an AD mouse model. The subiculum is the major output structure of the hippocampus and is among the earliest AD-impacted brain regions. We hypothesize that age-progressive alterations also occur in the neural circuit organization of the subiculum in the 5xFAD mouse model. To comprehensively map cell-type-specific circuit inputs, we utilized the novel viral-genetic tool of monosynaptic rabies tracing. We quantitatively assessed and compared the circuit connectivity of subiculum excitatory neurons in age-matched C57BL6 control and 5xFAD model mice at young and middle ages (3-4 months vs 8-9 months) in both sexes. The major subiculum input brain regions mapped by rabies tracing include hippocampal subregions, medial septum and diagonal band (MS-DB), subiculum (SUB), post subiculum (post SUB), visual (VIS) cortex, auditory (AUD) cortex, entorhinal cortex (EC), thalamus, and temporal association cortex (TeA). Our results reveal significant alterations in local and long-range circuit connections to the subiculum in AD model mice. The overall brain-wide connectivity strengths of subiculum inputs in aged AD model mice are weaker than in wild type mice. There are significant age and sex differences in the connectivity strengths of multiple input regions, including the hippocampal CA1, CA2, MS-DB, thalamus, RSC, VIS, AUD, and TeA. Our work provides new insights into subiculum- directed neural circuit mechanisms during AD progression and supports neural circuit disruptions as a prominent feature of AD.

Role of microglial extracellular vesicles in the propagation of early synaptic dysfunction in Alzheimer’s disease

AbstractBackgroundSynaptic dysfunction is an early mechanism in Alzheimer’s disease (AD) which involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown. We hypothesised that large extracellular vesicles (EVs) released by microglia may be responsible for these early events in AD.MethodLarge EVs carrying Aβ peptides (Aβ‐EVs) were obtained from primary microglia exposed to Aβ42. Optical manipulation was combined with time lapse imaging to study EV‐neuron interaction. Then, EVs were stereotaxically injected into naïve mice entorhinal cortex (EC), a vulnerable region in AD, to evaluate: i) long‐term potentiation (LTP) in EC and its main target region, the dentate gyrus of the hippocampus (DG), through field potential extracellular recordings in slices; ii) possible alterations in cortico‐hippocampal network activity by chronic EEG recordings; iii) progressive memory impairment in behavioural tasks. Finally, taking advantage of high‐resolution accurate‐mass spectrometry SWATH™‐MS, we investigated the molecular differences between Aβ‐ and ctrl‐EVs (from cells not exposed to Aβ). The influence of mesenchymal stem cell (MSC) indirect co‐colture with microglia primed with Aβ on cell phenotype, EVs and functions is also being explored.ResultAβ‐EVs were able to move along the axonal surface more efficiently than ctrl‐EVs and predominantly in an anterograde direction, altering dendritic spine morphology in vitro. LTP was impaired in the EC 1h after Aβ‐EV (but not ctrl‐EV) local injection, while 24h later LTP was impaired also in the DG, indicating a spreading of synaptic dysfunction between connected regions. This translated into network alterations and progressive memory deficits. Interestingly, Aβ42 alone was unable to spread alterations. Aβ‐EVs limited in their motion could neither propagate impairment nor cause network abnormalities, thus implicating Aβ‐EV extracellular motion in these processes. Proteomic analysis provided insights into the molecular mechanisms underneath Aβ‐EV motion at the neuronal surface.ConclusionOur data provide evidence of the involvement of microglial EVs in early synaptic dysfunction in AD, through a new mechanism ‐ extracellular motion at the neuronal surface ‐ not implying EV internalization, paving the way for novel therapeutic strategies. Reference: Gabrielli et al., Brain, 2022 https://doi.org/10.1093/brain/awac083 Fundings: 2018‐AARF‐588984, Horizon2020#874721PREMSTEM

Clinical Reasoning: A 62-year-old Man Presented with Right Left Disorientation and Progressive Memory Impairment

Clinical Reasoning: A 62-year-old Man Presented with Right Left Disorientation and Progressive Memory Impairment

Metabolic biomarkers for Alzheimer's disease: A mini review

Alzheimer's disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia worldwide, which characterized by progressive cognitive decline, memory impairment, and changes in behavior and personality. The prevalence of AD is expected to rise significantly in the coming decades due to the aging population, making it a major public health concern. Mounting evidence suggests that metabolic dysregulation plays a critical role in the pathogenesis of AD. In this mini review, we provide an overview of the current understanding of the interplay between metabolism and AD. Specifically, we explore the dysregulation of glucose metabolism, lipid metabolism, amino acid metabolism, and nitrogen oxide synthesis pathways in AD. These metabolic alterations have been identified as potential biomarkers for early diagnosis and prognosis of AD. Additionally, we discuss the current status of research in this field, including the advancements in metabolomics and imaging techniques that have allowed for the identification and validation of metabolic biomarkers.

Neuroinflammation in Alzheimer's Disease: A Potential Role of Nose-Picking in Pathogen Entry via the Olfactory System?

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. Many possible factors might contribute to the development of AD, including amyloid peptide and tau deposition, but more recent evidence suggests that neuroinflammation may also play an-at least partial-role in its pathogenesis. In recent years, emerging research has explored the possible involvement of external, invading pathogens in starting or accelerating the neuroinflammatory processes in AD. In this narrative review, we advance the hypothesis that neuroinflammation in AD might be partially caused by viral, bacterial, and fungal pathogens entering the brain through the nose and the olfactory system. The olfactory system represents a plausible route for pathogen entry, given its direct anatomical connection to the brain and its involvement in the early stages of AD. We discuss the potential mechanisms through which pathogens may exploit the olfactory pathway to initiate neuroinflammation, one of them being accidental exposure of the olfactory mucosa to hands contaminated with soil and feces when picking one's nose.

Pentoxifylline as Add-On Treatment to Donepezil in Copper Sulphate-Induced Alzheimer’s Disease-Like Neurodegeneration in Rats

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is characterized by behavioral, cognitive, and progressive memory impairments. Extensive neuronal loss, extracellular accumulation of insoluble senile amyloid-β (Aβ) plaques, and intracellular neurofibrillary tangles (NFTs) are the major pathological features. The present study aimed to investigate the therapeutic effect of donepezil (DON) and pentoxifylline (PTX) in combination to combat the neurodegenerative disorders (experimental AD) induced by CuSO4 intake in experimental rats. Thirty adult male Wistar rats (140–160 g) were used in this study. AD was first induced in rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. The AD group received no further treatment. Oral treatment with DON (10 mg/kg/day), PTX (100 mg/kg/day), or DON + PTX for the other three groups was started from the 10th week of CuSO4 intake for 4 weeks. Cortex markers like acetylcholine (ACh), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) and hippocampus markers like β-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), Clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 were measured. The histopathology studies were done by using hematoxylin and eosin and Congo red stains as well as immunohistochemistry for neurofilament. CuSO4 induced adverse histological and biochemical changes. The histological injury in the hippocampus was inhibited following the administration of the DON and PTX. The brain tissue levels of AChE, MDA, BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α were significantly increased, while brain tissue levels of ACh, TAC, and Bcl-2 were significantly decreased in CuSO4-treated rats as compared with the untreated control group. The effects induced by either DON or PTX on most studied parameters were comparable. Combined treatment of DON and PTX induced remarkable results compared with their individual use. However, more clinical and preclinical studies are still required to further confirm and prove the long-term efficacy of such combination.

Rubus fruticosus leaf extract inhibits vascular dementia-induced memory impairment and neuronal loss by attenuating neuroinflammation.

Vascular dementia (VaD) is characterized by progressive memory impairment, which is associated with microglia-mediated neuroinflammation. Polyphenol-rich natural plants, which possess anti-inflammatory activities, have attracted scientific interest worldwide. This study investigated whether Rubus fruticosus leaf extract (RFLE) can attenuate VaD. Sprague-Dawley rats were separated into five groups: SO, sham-operated and treated with vehicle; OP, operated and treated with vehicle; RFLE-L, operated and treated with low dose (30 mg/kg) of RFLE; RFLE-M, operated and treated with medium dose (60 mg/kg) of RFLE; and RFLE-H, operated and treated with high dose (90 mg/kg) of RFLE. Bilateral common carotid artery and hypotension were used as a modeling procedure, and the RFLE were intraorally administered for 5 days (preoperative 2 and postoperative 3 days). The rats then underwent memory tests including the novel object recognition, Y-maze, Barnes maze, and passive avoidance tests, and neuronal viability and neuroinflammation were quantified in their hippocampi. The results showed that the OP group exhibited VaD-associated memory deficits, neuronal death, and microglial activation in hippocampi, while the RFLE-treated groups showed significant attenuation in all above parameters. Next, using BV-2 microglial cells challenged with lipopolysaccharide (LPS), we evaluated the effects of RFLE in dynamics of proinflammatory mediators and the upstream signaling pathway. RFLE pretreatment significantly inhibited the LPS-induced release of nitric oxide, TNF-α, and IL-6 and upregulation of the MAPKs/NF-κB/iNOS pathway. Collectively, we suggest that RFLE can attenuate the histologic alterations and memory deficits accompanied by VaD, and these roles are, partly due to the attenuation of microglial activation.

Multi-layered transcriptomic analysis reveals a pivotal role of FMR1 and other developmental genes in Alzheimer's disease-associated brain ceRNA network

Alzheimer's disease (AD) is an increasingly neurodegenerative disorder that causes progressive cognitive decline and memory impairment. Despite extensive research, the underlying causes of late-onset AD (LOAD) are still in progress. This study aimed to establish a network of competing regulatory interactions involving circular RNAs (circRNAs), microRNAs (miRNAs), RNA-binding proteins (RBPs), and messenger RNAs (mRNAs) connected to LOAD. A systematic analysis of publicly available expression data was conducted to identify integrated differentially expressed genes (DEGs) from the hippocampus of LOAD patients. Subsequently, gene co-expression analysis identified modules comprising highly expressed DEGs that act cooperatively. The competition between co-expressed DEGs and miRNAs/RBPs and the simultaneous interactions between circRNA and miRNA/RBP revealed a complex ceRNA network responsible for post-transcriptional regulation in LOAD. Hippocampal expression data for miRNAs, circRNAs, and RBPs were used to filter relevant relationships for AD. An integrated topological score was used to identify the highly connected hub gene, from which a brain core ceRNA subnetwork was generated. The Fragile X Messenger Ribonucleoprotein 1 (FMR1) coding for the RBP FMRP emerged as the prominent driver gene in this subnetwork. FMRP has been previously related to AD but not in a ceRNA network context. Also, the substantial number of neurodevelopmental genes in the ceRNA subnetwork and their related biological pathways strengthen that AD shares common pathological mechanisms with developmental conditions. Our results enhance the current knowledge about the convergent ceRNA regulatory pathways underlying AD and provide potential targets for identifying early biomarkers and developing novel therapeutic interventions.