Search Results (3,349)

Mild cognitive impairment (MCI) represents a heterogeneous state between normal aging and dementia, with varied transition pathways. While factors influencing MCI progression are known, their role in cognitive reversal is unclear. This study analyzed 756 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants, classified as progressive MCI (pMCI, N = 272, mean age = 75.10 ± 7.34 years), reversible MCI (rMCI, N = 52, mean age = 69.94 ± 7.98 years) and stable MCI (sMCI, N = 432, mean age = 73.34 ± 7.44 years) based on 36-month follow-up. We compared demographic, lifestyle, clinical, cognitive, neuroimaging, and biomarker data across groups and developed a prediction model. Patients in the rMCI group were significantly younger and had a higher level of education compared with those in the pMCI group. Memory, general cognition, daily functional activities, and hippocampal volume effectively distinguished all three groups. In contrast, Aβ, tau, and other brain regions were able to distinguish only between progressive and non-progressive cases. Informant-reported Everyday Cognition (Ecog) scales outperformed self-reported Ecog scales in differentiating subtypes and predicting progression. Multinomial regression revealed that higher education, larger hippocampal volume, and lower daily functional impairment were associated with reversion, whereas APOE ε4, poorer memory, and greater brain atrophy predicted progression (model accuracy: 78%). The results confirm the significant utility of hippocampal volume, education level, and daily functional activities for assessing baseline disparities and predicting reversion. This study highlights the differential contributions of cognitive abilities and brain regions on MCI reversal, advancing understanding of MCI heterogeneity and providing evidence for precise diagnosis and treatment in early MCI. Full article

Background: Studies have shown that input comparison in the hippocampus between the Schaffer collateral (SC) input in apical dendrites and the perforant path (PP) input in the apical tufts dramatically changes the activity of pyramidal cells (PCs). Equally, dendritic inhibition was shown to control PC activity by minimizing the depolarizing signals in their dendritic trees, controlling the synaptic integration time window, and ensuring temporal firing precision. Objectives: We computationally investigated the diverse roles of inhibitory synapses on the PC dendritic arbors of a CA1 microcircuit model in mnemonic retrieval during the co-occurrence of SC and PP inputs. Results: Our study showed inhibition in the apical PC dendrites mediated thresholding of firing during memory retrieval by restricting the depolarizing signals in the dendrites of non-engram cells, thus preventing them from firing, and ensuring perfect memory retrieval (only engram cells fire). On the other hand, inhibition in the apical dendritic tuft removed interference from spurious EC during recall. When EC drove only the engram cells of the SC input cue, recall was perfect under all conditions. Removal of apical tuft inhibition had no effect on recall quality. When EC drove 40% of engram cells and 60% of non-engram cells of the SC input cue, recall was disrupted, and this disruption was worse when the apical tuft inhibition was removed. When EC drove only the non-engram cells of the cue, then recall was perfect again but only when the population of engram cells was small. Removal of the apical tuft inhibition disrupted recall performance when the population of engram cells was large. Conclusions: Our study deciphers the diverse roles of dendritic inhibition in mnemonic processing in the CA1 microcircuit of the rat hippocampus. Full article

Activation of cGAS, a receptor recognizing cytosolic DNA, in macrophages might be associated with rabies (an RNA virus) through mitochondrial damage. A similar mortality rate was observed between cGAS-deficient (cGAS-/-) and wild-type (WT) mice post-CVS-11 strain injection. However, 2 out of 12 cGAS-/- mice (but not WT) survived for 15 days post-injection. At 7 days post-infection, less severe brain inflammation in cGAS-/- mice was demonstrated by the viral abundance in the hippocampus, the expression of proinflammatory genes (TNF-α and IL-1β), and the Evans blue dye assay (blood–brain barrier defect) with the presence of higher anti-inflammatory genes (TGF-β and arginase-1). Fecal Proteobacteria was more prominent in the infected WT mice, while serum cytokines (TNF-α and IL-1β) were similar in both mouse strains. There were less prominent responses against the rabies virus in cGAS-/- macrophages than in WT cells, as indicated by supernatant IL-6 and the gene expression of TLR-3, RIG-1, MDA-5, and iNOS. On the other hand, mitochondrial injury and cGAS activation were more prominent in WT macrophages over cGAS-/- cells, as indicated by cGAS expression, supernatant cGAMP (a secondary messenger of cGAS), and mitochondrial oxidative stress (MitoSox) together with a decrease in mitochondrial DNA and maximal respiration (extracellular flux analysis). In conclusion, (i) rabies-damaged mitochondria led to cGAS activation that was less severe in cGAS-/- than in WT, (ii) rabies-induced dysbiosis was demonstrated, and (iii) cGAS manipulation and gut–brain axis-associated inflammation warrants further investigation. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β (Aβ) pathology, synaptic degeneration, impaired neurogenesis, and chronic neuroinflammation. KBN2202, a small-molecule salicylic acid derivative [2-[(2-naphthalen-1-yloxy)ethyl]amino]-4-hydroxybenzoic acid], was investigated for its potential as a multi-target therapeutic agent in advanced-stage AD. To this end, 9-month-old 5xFAD mice with established AD-like pathology received daily oral KBN2202 (5 or 20 mg/kg) or vehicle for 12 weeks. KBN2202 demonstrated broad histopathological benefits. It preserved hippocampal CA1 cytoarchitecture and increased dendritic length in cortical neurons. Neurogenic activity was also enhanced, with elevated doublecortin (DCX) expression in the subventricular zone (SVZ). At the molecular level, KBN2202 reduced amyloid precursor protein C-terminal fragments (APP-CTFs), key intermediates in amyloidogenic processing, and histological staining confirmed a significant reduction in fibrillar and diffuse Aβ plaque burden in the cortex and hippocampus. Furthermore, KBN2202 attenuated astrocytic and microglial activation, indicating suppression of chronic neuroinflammation. In behavioral assessments, KBN2202 significantly improved recognition memory in the novel object recognition (NOR) test, while Y-maze performance remained unchanged. Overall, the compound exhibited robust neuroprotective, pro-neurogenic, anti-amyloid, and anti-inflammatory effects. These findings support the therapeutic potential of KBN2202 as a multi-functional candidate for symptomatic-stage AD. Full article

The streptozotocin (STZ) experimental model of sporadic Alzheimer’s disease (SAD), the most prevalent form of this type of dementia, has become a valuable tool to study the behavioral and morphological changes that occur during the gradual development of this pathology. We used the STZ experimental model in combination with the novel object recognition test (NORT) and immunohistochemical techniques to evaluate the recognition memory decline and morphological alterations in memory-related structures (hippocampus and cortex). Our analysis included five different time points after intracerebroventricular (ICV) administration of 3 mg/kg of STZ or artificial cerebrospinal fluid (aCSF) as a control. The time points included three distinct stages: early (15 and 30 days), intermediate (60 days), and late (90 and 120 days). We found that recognition memory impairment started in the intermediate stage and persisted through the later stages. Morphologically, we detected significant astrogliosis starting in the early stages, whereas cholinergic changes began in the intermediate stage. No neuronal loss was observed at any of the time points analyzed. Our results further support the hypothesis that astrogliosis constitutes an initial pathological event that may compromise the hippocampal cholinergic system and can contribute to the onset of recognition memory deficits. Full article

Background/Objectives: Marine-derived bioactive peptides have been reported to possess blood pressure-regulatory effects. However, most studies have focused on the antihypertensive effects after single-dose administration, and research on long-term administration and its protective effects against hypertension-induced tissue damage remains limited. Therefore, this study aimed to investigate the long-term antihypertensive efficacy of IGTGIPGIW, a bioactive peptide derived from Hippocampus abdominalis (H. abdominalis), and its protective effects on hypertension-related tissue damage. Methods: To evaluate the blood pressure-regulatory effects, spontaneously hypertensive rats (SHRs) were orally administered a high-dose (50 mg/kg) IGTGIPGIW peptide group (H-IGTGIPGIW) for 8 weeks. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were monitored weekly. Serum levels of angiotensin II (Ang II), angiotensin-converting enzyme (ACE), and angiotensin-converting enzyme 2 (ACE2) were measured to assess the peptide’s regulatory effects on the renin–angiotensin system. Histological analyses of the aorta and heart tissues were performed to evaluate the protective effects against hypertension-induced tissue damage. Results: After 8 weeks of treatment, H-IGTGIPGIW significantly reduced SBP, DBP, and MAP compared with SHRs. Serum Ang II and ACE levels were significantly decreased, while ACE2 levels were significantly increased. Histological analyses demonstrated that IGTGIPGIW alleviated aortic wall thickening and reduced renal and cardiac tissue damage in SHR. Conclusions: IGTGIPGIW, a bioactive peptide derived from H. abdominalis, effectively regulated blood pressure by modulating serum Ang II, ACE, and ACE2 levels. Moreover, it protected against hypertension-induced aortic, renal and cardiac tissue damage, suggesting its potential as a functional ingredient for managing hypertension. Full article

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron (MN) degeneration, frequently overlapping with frontotemporal dementia (FTD). Protein aggregation is a hallmark of these disorders, yet the role of aggregates in ALS pathogenesis remains unclear. Previously, stomatin-like protein 2 (SLP2) and prohibitin (PHB) aggregates were identified in a model of CHCHD10-related ALS (Chchd10^S59L/+ mice). This study raises the question of the presence and possible involvement of these aggregates in ALS beyond CHCHD10-associated motor neuron disease (MND). Using immunohistofluorescence, we analyzed SLP2/PHB expression in the spinal MNs and hippocampus of two ALS mouse models: Fus^ΔNLS and Sod1^G86R. Additionally, post-mortem spinal cord tissues from 27 ALS and ALS-FTD patients were analyzed. SLP2/PHB aggregates were identified in spinal MNs and the hippocampus of Fus^ΔNLS mice but not in Sod1^G86R mice. In ALS patients, SLP2/PHB aggregation was observed in four cases, including two with C9ORF72 mutations. Interestingly, aggregates were absent in SOD1-associated ALS patients. These findings suggest that SLP2/PHB aggregation is not specific to CHCHD10 variants but may contribute to the pathogenesis of ALS from different origins. The age-related accumulation of these aggregates highlights their potential role in disease progression and as therapeutic targets. Future studies should investigate their mechanistic contributions across different ALS subtypes. Full article

Multi-Wall Carbon Nanotubes (MWCNTs) are under investigation for their use in biomedical applications, especially in neurological diseases, due to their electrochemical properties. Nevertheless, conflicting results have cast doubt on their safety. To advance their translational potential, we evaluated the cytotoxicity of two MWCNT samples in vivo in both vertebrate and invertebrate animal models. Pristine MWCNTs were, in part, used as prepared (MWCNTs), and, in part, annealed at 2400 °C (a-MWCNTs). The two samples differ in their electrochemical properties: MWCNTs are not electro-conductive, while a-MWCNTs are electro-conductive and negatively charged on their surface. We evaluated the effects of both intranasally delivered MWCNTs on several key markers of cell viability in the olfactory bulbs and hippocampus from healthy adult Wistar rats, as well as their impact on lifespan, genotoxicity, oxidative stress, and aging-related functional markers in the nematode Caenorhabditis elegans. Neither of the two MWCNT samples was cytotoxic towards neuronal cells in the hippocampus. In olfactory bulbs, only electro-conductive a-MWCNTs interacted with two positively charged mitochondrial proteins: Translocase of Outer Mitochondrial Membrane 20 (TOM20) and Cytochrome C (CytC). In C. elegans, neither type of MWCNT affected lifespan or brood size, and cytosolic ROS levels remained unchanged. Notably, treated worms exhibited a significantly delayed aging phenotype. Metallic MWCNTs are biocompatible in living organisms and possess the potential to modulate neural cells functioning in vivo. Full article

Lipid debris generated after ischemic stroke overwhelms myeloid cells, leading to foam cell-like dysfunction and chronic neuroinflammation. 2-hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol-mobilizing agent, has been shown to improve recovery and reduce chronic inflammation after stroke by enhancing lipid processing and cholesterol efflux in infarcts. To identify plasma biomarkers of HPβCD activity and gain mechanistic insight into lipid pathway modulation, aged (21-month-old) male mice underwent the distal middle cerebral artery occlusion + hypoxia (DH) model of stroke and received 2 g/kg HPβCD twice daily beginning 1 d after stroke. Plasma metabolomic and lipidomic profiling was performed 4 d after stroke using untargeted (Global Discovery) and targeted (Complex Lipid, Oxysterols, and Lipid Mediators of Inflammation) panels. Acute neuroprotection was assessed by magnetic resonance imaging (MRI) quantification of infarct, ventricle, and hippocampus volumes 2 d after stroke and by plasma neurofilament light (NfL) levels 4 d after stroke. HPβCD treatment did not provide acute neuroprotection; however, HPβCD did induce distinct plasma metabolomic and lipidomic signatures, including decreases in sphingolipids, cholesterol, long-chain fatty acids, 4β-hydroxycholesterol, 7-dehydrocholesterol, and 8-dehydrocholesterol and increases in 27-hydroxycholesterol and 7α-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA), consistent with enhanced cholesterol efflux and metabolism. Pro-inflammatory oxylipins were also suppressed by HPβCD treatment. These results support the role of HPβCD in promoting lipid debris clearance and suppressing inflammatory lipid pathways after stroke and, together with prior studies demonstrating improved long-term recovery, highlight HPβCD as a biomarker-supported therapeutic candidate for stroke recovery. Full article

Memory consolidation is the process by which newly acquired experiences are stabilized into long-term memory, involving coordinated cellular and network-level activity across brain regions such as the hippocampus and prefrontal cortex. Dysregulation of this process has been implicated in psychiatric disorders including post-traumatic stress disorder (PTSD), which is characterized by the over-consolidation of traumatic memories. LIM kinase 1 (LIMK1), a key regulator of synaptic plasticity, is believed to play an important role in memory consolidation across hippocampal–cortical circuits. In this study, we investigated the function of LIMK1 using Limk1 knockout mice. Behavioral tests such as the novel object location memory task revealed significant memory impairments in knockout animals. In vivo recordings during sleep showed disrupted communication between the hippocampus and prefrontal cortex, suggesting impaired systems-level consolidation. Furthermore, in an underwater trauma exposure model, pharmacological inhibition of LIMK1 with LIMK-i3 alleviated trauma-induced behavioral abnormalities. These findings highlight LIMK1 as a critical mediator of hippocampal–cortical memory consolidation and provide experimental evidence that LIMK1 inhibition can modulate maladaptive memory processes associated with PTSD-like symptoms. Full article

Maternal immune activation (MIA) is a recognized environmental risk factor for altered brain development, yet its early molecular consequences remain unclear. In this study, we examined total Tau, site-specific Tau phosphorylation, and selected synaptic proteins in one-month-old female mouse offspring exposed prenatally to MIA evoked by poly(I:C), a synthetic mimetic of viral dsRNA. Our analyses revealed a consistent reduction in Tau phosphorylation at Ser416 across multiple brain regions, including the cortex, hippocampus, and cerebellum, without changes in total Tau levels or other phosphorylation sites. Among synaptic markers, only Shank3 levels were decreased, and this effect was confined to the cerebellum. No additional robust alterations were detected at this stage of development. These findings suggest that Tau hypophosphorylation at Ser416 may represent an early and widespread molecular footprint of MIA, whereas cerebellar Shank3 downregulation points to a region-specific vulnerability of synaptic pathways. While the study is limited to female offspring and a single postnatal time point, the data provide new insights into subtle molecular signatures that could precede or accompany later functional outcomes. Our results highlight Tau phosphorylation and Shank3 expression as potential molecular markers of prenatal immune stress, warranting further longitudinal and sex-comparative studies to clarify their relevance for neurodevelopmental trajectories. Full article

Background/Objectives: Cerebral ischemia and reperfusion injury, induced by bilateral common carotid artery occlusion and reperfusion (BCCAO/R), cause extensive neuronal damage and cognitive impairment. Bouvardia ternifolia (BtD), a plant known for its anti-inflammatory and neuroprotective effects, may offer therapeutic benefits against ischemic injury. This study aimed to evaluate the neuroprotective effects of BtD root extract on neuronal integrity, oxidative stress, and p53 protein expression following global cerebral ischemia in rats. Methods: Adult male Sprague Dawley rats were subjected to the BCCAO/R procedure for 60 min, followed by six days of reperfusion. Experimental groups included BCCAO/R+BtD, BCCAO/R+silymarin (reference control), BCCAO/R+vehicle, and sham controls. Neuronal morphology in the cortex, striatum, hippocampus, and cerebellum was assessed histologically. Oxidative stress markers, including reactive oxygen species (ROS), lipid peroxidation (LPO), reduced glutathione (GSH), and superoxide dismutase (SOD), were measured, along with the expression of p53 protein. Results: Treatment with BtD significantly decreased oxidative stress markers—LPO (82.2%), ROS (88.2%), GSH (66.5%), and SOD (54%)—and reduced p53 expression levels by 75%. Histological evaluation revealed that neurons in the BCCAO/R+BtD and BCCAO/R+silymarin groups maintained normal morphology, characterized by elongated cells and well-defined nuclei. In contrast, the BCCAO/R+vehicle group exhibited marked neuronal damage, including pyknosis, nuclear fragmentation, and interstitial edema, particularly in the hippocampal CA1 and cortical regions. BtD treatment significantly preserved neuronal structure and enhanced antioxidant defenses. Conclusions:Bouvardia ternifolia extract demonstrates neuroprotective potential in cerebral ischemia by maintaining neuronal architecture, reducing oxidative stress, and modulating p53 expression, supporting its therapeutic relevance in ischemia–reperfusion injury. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and depression, are marked by progressive neuronal dysfunction and loss, yet current treatments remain largely symptomatic with limited disease-modifying efficacy. Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent. Its receptor, GLP-1R, is expressed in key brain regions implicated in cognition, emotion, and motor control, including the hippocampus, frontal cortex, and substantia nigra. GLP-1R agonists (GLP-1RAs) activate multiple intracellular signaling cascades—cAMP/PKA, PI3K/Akt, and MAPK pathways—that collectively promote neuronal survival, enhance synaptic plasticity, reduce oxidative stress, inhibit apoptosis, and modulate neuroinflammation. These agents also regulate autophagy, promote remyelination, and reprogram microglial phenotypes toward anti-inflammatory states. Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors. Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood–brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials. These studies report attenuation of cortical atrophy, preservation of cerebral glucose metabolism, and improvements in quality of life, though changes in core AD biomarkers remain inconclusive. Ongoing large-scale trials (e.g., EVOKE, ELAD) are further exploring their therapeutic impact. This review consolidates the mechanistic basis and translational potential of GLP-1RAs in age-related neurodegenerative diseases, highlighting both their promise and the challenges that must be addressed in future clinical applications. Full article

Among mouse models of neurological disease, Theiler’s murine encephalomyelitis virus (TMEV) provides a unique platform by using a naturally occurring viral trigger, paralleling the role of infections like Epstein–Barr virus in multiple sclerosis (MS). Just as not all individuals with predisposing viral infections develop the same neurological disease, not all mouse strains develop the same diseases following TMEV infection, so susceptibility is dictated by genetic background. For example, certain sets of alleles, called haplotypes, of the major histocompatibility complex (MHC) region have been associated with susceptibility to TMEV-induced demyelination (TVID) and MS. However, our previous work revealed that these MHC susceptibility haplotypes are not the sole contributors to TMEV-induced diseases in all mice. We infected mice from the genetically diverse Collaborative Cross (CC), a resource designed to reflect human population-level genetic variation. All 15 CC strains tested exhibited some form of neurological phenotype or CNS lesion following TMEV infection. However, chronic radiculoneuropathy characterized by axonal degeneration with myelin loss was observed in the CNS of only two strains, CC002 and CC023, which had markedly different immune responses and clinical profiles throughout the course of infection. Moreover, the pathology seen in CC002 and CC023 was not the same as what is typically seen in TVID. We used previous results from RNA sequencing of the hippocampus and spinal cord to test our hypothesis that myelin loss in these strains resulted from the convergent biological effects of multiple genetic risk variants, many previously unassociated with TMEV-induced diseases. These findings identify novel genetic targets and demonstrate the utility of genetically diverse models for uncovering complex neuroimmune interactions. Full article

Background/Objectives: Visual dysfunction emerges during the mild cognitive impairment stage of early Alzheimer’s disease (AD). While previous studies have primarily focused on retinal pathology, the early pathological progression across central nodes of the visual pathway remains inadequately characterized. This study examined regional pathological and structural alterations throughout the visual pathway at different disease stages in APP/PS1 transgenic mice aged 3, 6, and 9 months. Methods: Cognitive function was first assessed using novel object recognition and Y-maze tests to stage disease progression. Subsequently, Histological staining was employed to systematically analyze pathological features in the retina, lateral geniculate nucleus (LGN), and primary visual cortex (V1). Evaluated parameters encompassed β-amyloid (Aβ) deposition levels, microglial activation status, total neuronal counts, parvalbumin (PV)-positive neuron numbers, and tissue thickness measurements of the retina and V1. Results: At 6 months, mice exhibited an early symptomatic phenotype with selective spatial working memory deficits while long-term memory remained intact. Pathological analysis revealed concurrent Aβ deposition and microglial activation in V1, retina, and hippocampus by 6 months, whereas comparable LGN changes manifested only at 9 months, demonstrating regional heterogeneity in disease progression. V1 neuronal populations remained stable through 6 months but showed significant reduction by 9 months, though PV-positive neurons were selectively preserved. The LGN exhibited no neuronal loss even at 9 months. Gross structural thickness of both retina and V1 remained unchanged across all timepoints. Conclusions: These findings demonstrate that early visual system pathology in this AD model extends beyond the retina. The primary visual cortex exhibits early pathological changes (Aβ deposition and neuroinflammation) concurrent with hippocampal involvement, progressing to selective neuronal loss in later stages. The severity and selectivity of V1 pathology surpass those observed in other visual pathway nodes, including the LGN. Thus, V1 could represent not merely an affected region but a promising site for elucidating early cortical AD mechanisms and developing novel diagnostic biomarkers. Full article