Search Results (65)

The renin-angiotensin system (RAS) has evolved from being considered solely a peripheral endocrine system for cardiovascular control to being recognized as a complex molecular network with important functions in the central nervous system (CNS) and peripheral nervous system (PNS). Here we examine the organization, mechanisms of action, and clinical implications of cerebral RAS in physiological conditions and in various neurological pathologies. The cerebral RAS operates autonomously, synthesizing its main components locally due to restrictions imposed by the blood–brain barrier. The key elements of the system are (pro)renin; (pro)renin receptor (PRR); angiotensinogen; angiotensin-converting enzyme types 1 and 2 (ACE1 and ACE2); angiotensin I (AngI), angiotensin II (AngII), angiotensin III (AngIII), angiotensin IV (AngIV), angiotensin A (AngA), and angiotensin 1-7 (Ang(1-7)) peptides; RAS-regulating aminopeptidases; and AT1 (AT1R), AT2 (AT2R), AT4 (AT4R/IRAP), and Mas (MasR) receptors. More recently, alamandine and its MrgD receptor have been included. They are distributed in specific brain regions such as the hypothalamus, hippocampus, cerebral cortex, and brainstem. The system is organized into two opposing axes: the classical axis (renin/ACE1/AngII/AT1R) with vasoconstrictive, proinflammatory, and prooxidative effects, and the alternative axes AngII/AT2R, AngIV/AT4R/IRAP, ACE2/Ang(1-7)/MasR and alamandine/MrgD receptor, with vasodilatory, anti-inflammatory, and neuroprotective properties. This functional duality allows us to understand its role in neurological physiopathology. RAS dysregulation is implicated in multiple neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and neuropsychiatric disorders such as depression and anxiety. In brain aging, an imbalance toward hyperactivation of the renin/ACE1/AngII/AT1R axis is observed, contributing to cognitive impairment and neuroinflammation. Epidemiological studies and clinical trials have shown that pharmacological modulation of the RAS using ACE inhibitors (ACEIs) and AT1R antagonists (ARA-II) not only controls blood pressure but also offers neuroprotective benefits, reducing the incidence of cognitive decline and dementia. These effects are attributed to direct mechanisms on the CNS, including reduction of oxidative stress, decreased neuroinflammation, and improved cerebral blood flow. Full article

Alzheimer’s dementia (AD) is a disease of the ageing brain. It begins in the hippocampal region with the epicentre in the entorhinal cortex, then gradually extends into adjacent brain areas involved in memory and cognition. The events which initiate the damage are unknown and under intense investigation. Localization to the hippocampus can now be explained by anatomical features of the blood vessels supplying this region. Blood supply and hence oxygen delivery to the area are jeopardized by poor flow through narrowed arteries. In genomic and metabolomic studies, the respiratory chain and mitochondrial pathways which generate ATP were leading pathways associated with AD. This review explores the notion that ATP depletion resulting from hippocampal hypoperfusion has a prime role in initiating damage. Sections cover sensing of ATP depletion and protective responses, vulnerable processes with very heavy ATP consumption (the malate shuttle, the glutamate/glutamine/GABA (γ-aminobutyric acid) cycle, and axonal transport), phospholipid disturbances and peroxidation by reactive oxygen species, hippocampal perfusion and the effects of hypertension, chronic hypoxia, and arterial vasospasm, and an overview of recent relevant genomic studies. The findings demonstrate strong scientific arguments for the proposal with increasing supportive evidence. These lines of enquiry should be pursued. Full article

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

Background/Objectives: Major Depression (MD) is a common disorder that has significant social and economic impacts. Approximately 30% of all MD patients are refractory to common treatments, representing a major obstacle to managing the impacts of depression. One potential explanation for the incomplete treatment efficacy in MD is a substantial divergence in the mechanisms and brain networks involved in different subtypes of the disorder. The aim of this study was to identify novel brain regional targets for MD clinical screening using a gene-informed approach. Methods: A new analysis pipeline, called “Analysis Tool for Local Association of Neuronal Transcript Expression” (ATLANTE), was generated and validated. The pipeline identifies brain regions based on the shared high expression of user-generated gene lists; in this study, the pipeline was applied to discover brain regions that may be significant to MD. Results: Nine discrete brain regions of interest to MD were identified, including the temporal pole, anterior transverse temporal gyrus (Heschl’s gyrus), olfactory tubercle, ventral tegmental area, postcentral gyrus, CA1 of the hippocampus, olfactory area, perirhinal gyrus, and posterior insular cortex. The application of network and clustering analyses identified genes of special importance, including, most notably, PRKN. Conclusions: This study provides two major insights. The first is that several brain regions have unique MD-associated genetic architectures, indicating a potential explanation for subtype-specific dysfunction. The second insight is that the PRKN gene, which is strongly associated with Parkinson’s disease, is a key player amongst the MD-associated genes. These findings reveal novel targets for the clinical screening of depression and reinforce a mechanistic connection between MD and Parkinson’s disease. Full article

Abnormal deposition of β-amyloid (Aβ) is a core pathological feature of Alzheimer’s disease (AD). Syndecan-3 (SDC3), a type I transmembrane heparan sulfate proteoglycan (HSPG), is abnormally overexpressed in the brains of AD patients and model animals, specifically accumulating in the peri-plaque region of amyloid plaques. However, its regulatory mechanism in the process of Aβ deposition remains unclear. This study aims to clearly define the role of SDC3 in Aβ aggregation and neuroinflammation, two critical processes in AD pathogenesis. Specifically, we investigate how SDC3 modulates Aβ aggregation and its interaction with neuroinflammatory pathways, which may contribute to the progression of AD. By elucidating the mechanisms underlying SDC3’s involvement in these processes, we seek to provide new insights into potential therapeutic targets for AD. In this study, a 5×FAD mouse model with downregulated SDC3 expression was constructed. Behavioral assessments and synaptic function tests were performed to explore the effects of SDC3 on cognition in 5×FAD mice. Immunofluorescence co-localization technology was utilized to analyze the pathological co-deposition of SDC3 and Aβ in the hippocampus, cortex, and meningeal blood vessels. Quantitative assessments of pro-inflammatory cytokines such as Tnf-α and Cxcl10 in the brain were performed through histopathological analysis combined with qPCR. Western blotting was used to examine the phosphorylation status of STAT1/STAT3 and the expression changes of IBA1/GFAP to systematically analyze the molecular mechanisms through which SDC3 regulates AD pathology. This study revealed that SDC3 expression was significantly upregulated in the brain regions of the 5×FAD model mice and co-localized pathologically with Aβ. Cell lineage tracing analysis showed that the elevated SDC3 expression primarily originated from glial cells. Behavioral and pathological results demonstrated that downregulation of SDC3 significantly improved cognitive dysfunction in the model mice and effectively reduced the Aβ burden in the brain. Molecular mechanism studies showed that downregulation of SDC3 reduced the phosphorylation of STAT1 and STAT3, thereby inhibiting the activation of the JAK-STAT and cGAS-STING signaling pathways, reducing the activation of microglia/astrocytes and suppressing the expression of pro-inflammatory cytokines such as Tnf-α and Cxcl10. This study reveals that SDC3 co-localizes with Aβ pathology and synergistically exacerbates neuroinflammation. Knockdown of SDC3 can simultaneously reduce both Aβ deposition and the release of inflammatory factors from glial cells. Mechanistic research indicates that SDC3 drives a “glial activation–cytokine release” vicious cycle through the JAK-STAT and cGAS-STING signaling pathways. These findings suggest that SDC3 may serve as a key hub coordinating amyloid pathology and neuroinflammation in AD, providing new insights for the development of combination therapies targeting the HSPG network. Full article

Endocannabinoids, acting primarily through CB1 receptors, are critical modulators of neuronal activity, influencing cognitive functions and emotional processing. CB1 receptors are highly expressed in the hippocampus, primarily on GABAergic interneurons, modulating the excitation/inhibition balance. Previous evidence suggests the functional heterogeneity of CB1 receptors along the dorsoventral axis of the hippocampus. However, it is not known whether CB1 receptors differentially modulate basic aspects of the local neuronal network along the hippocampus. This study investigated how CB1 receptor activation modulates excitability, paired-pulse inhibition (PPI), and short-term neuronal dynamics (STND) in the dorsal and ventral CA1 hippocampus under physiologically relevant conditions. Using extracellular recordings from hippocampal slices of male Wistar rats, we compared the effects of two CB1 receptor agonists, ACEA and WIN55,212-2, on network activity in the dorsal and ventral hippocampus. We found that both agonists significantly increased excitability and reduced PPI in the dorsal, but not the ventral, hippocampus. Similarly, CB1 receptor activation modulated STND more prominently in the dorsal hippocampus, reducing facilitation at low frequencies and reversing depression at high frequencies, whereas effects on the ventral region were minimal. These dorsoventral differences in the actions of cannabinoid receptor agonists occurred despite similar CB1 receptor expression levels in both regions, suggesting that functional differences arise from downstream mechanisms rather than receptor density. Pre-application of the GIRK channel blocker Tertiapin-Q occluded the effects of WIN55,212-2 on STND, indicating a significant role of GIRK channel-mediated signaling in CB1 receptor actions. These findings demonstrate that CB1 receptors modulate hippocampal circuitry in a region-specific manner, with the dorsal hippocampus being more sensitive to cannabinoid signaling, likely through differential engagement of intracellular signaling pathways such as GIRK channel activation. These results provide novel insights into how endocannabinoid signaling differentially regulates neuronal dynamics along the dorsoventral axis of the hippocampus. They also have important implications for understanding the role of cannabinoids in hippocampus-dependent behaviors. Full article

Epilepsy is a neurological disorder characterized by recurrent, unprovoked seizures, affecting millions worldwide. While anti-seizure medications serve as first-line treatment, approximately one-third of patients develop drug-resistant epilepsy (DRE), necessitating alternative interventions. Deep brain stimulation (DBS) has emerged as a promising therapy for DRE, particularly for patients who are ineligible for resective surgery. DBS involves stereotactic implantation of electrodes into target brain regions, such as the anterior nucleus of the thalamus (ANT), centromedian nucleus (CMT), and hippocampus (HC), to modulate aberrant neural activity and to reduce seizure frequency. Anesthesia plays a critical role in DBS implantation, influencing both patient safety and procedural success. The choice of anesthetic technique must balance patient comfort with the preservation of neurophysiological signals used for intraoperative electrode localization. A well-chosen anesthetic strategy can enhance the efficacy of electrode placement by minimizing patient movement and preserving critical neurophysiological signals for real-time monitoring. This precise targeting enhances safety via a reduction in perioperative risks and an improvement in long-term seizure control. Anesthetic considerations in epilepsy patients differ from those in movement disorders due to variations in their nuclei targets during DBS. Despite the increasing use of DBS for epilepsy following its FDA approval in 2018, research on anesthetic effects specific to this population remains limited. This narrative review, therefore, examines anesthetic approaches, pharmacological implications, potential complications, and evolving methods for DBS implantation in epilepsy patients, highlighting new insights and unique considerations in this population. Understanding these factors is essential for optimizing surgical outcomes and improving the safety and efficacy of DBS in epilepsy treatment. Full article

Calcium-binding proteins (CaBPs) are known to modulate neuronal excitability and calcium signaling, and they may play a role in the imbalances of excitation and inhibition of temporal lobe epilepsy (TLE). While parvalbumin and calretinin are well-characterized CaBPs, N-Terminal EF-Hand Calcium-Binding Protein 1 (NECAB1) remains understudied in epilepsy, despite its association with neurodegenerative conditions. In this study, we used fluorescent immunolabeling to determine the distribution of NECAB1, as well as its co-expression with parvalbumin and calretinin, in brain regions associated with the epileptic circuitry using a kainic acid-induced TLE model. Additionally, we examined the impact of levetiracetam and brivaracetam on NECAB1 expression. In our study, NECAB1-positive cells were prominently localized to the paraventricular nucleus of the thalamus (PVT), endopiriform nucleus (EPN), and amygdala in healthy brain regions involved in epileptic circuitry. A NECAB1–calretinin co-expressing subpopulation was detected in the amygdala, PVT, and hippocampus but was nearly absent in the EPN. In chronic epilepsy, NECAB1 expression was significantly upregulated in the PVT and bilaterally in the amygdala. These findings suggest that NECAB1 upregulation may compensate for epileptic hyperexcitability, potentially contributing to circuit remodeling via thalamocortical regulation and interneuron diversity. Levetiracetam and brivaracetam treatments partially reduced the NECAB1 density increase in TLE, indicating a modulatory effect on NECAB1 expression. Full article

Background and Objectives: Brain radionecrosis is an under-recognized but potentially life-altering late complication of radiotherapy in patients with locally advanced nasopharyngeal cancer. Temporal lobe radionecrosis and high-dose exposure to the hippocampus are strongly associated with cognitive decline and radiation-induced dementia, negatively impacting patients’ long-term quality of life (QoL). This study aimed to evaluate and compare radiation dose distributions to critical brain structures across three radiotherapy techniques—3D conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and volumetric-modulated arc therapy (VMAT)—in order to assess potential neurocognitive risks and support hippocampal-sparing protocols. Materials and Methods: Ten patients previously treated with 3D-CRT were retrospectively replanned using IMRT and VMAT techniques on the Eclipse v13.3 (VARIAN) planning system. Bilateral hippocampi and temporal lobes were delineated as organs at risk (OARs) according to the RTOG atlas, and dosimetric parameters including D_max, D_mean, and D_min were recorded. V7.3 values were evaluated for hippocampal avoidance regions. Results: While IMRT and VMAT provided improved target volume coverage and reduced high-dose exposure to many standard OARs, both techniques were associated with increased D_mean and D_min to the hippocampus and temporal lobes compared to 3D-CRT. The highest D_max values to the temporal lobes were observed in 3D-CRT plans, indicating a potential risk of radionecrosis. VMAT plans showed hippocampal mean doses exceeding 10 Gy in some cases, with V7.3 > 40%, breaching established neurocognitive risk thresholds. Conclusions: These findings support the routine delineation of the hippocampus and temporal lobes as OARs in radiotherapy planning for nasopharyngeal cancer. The implementation of hippocampal-sparing strategies, particularly in IMRT and VMAT, is recommended to reduce the risk of radiation-induced cognitive toxicity and preserve long-term QoL in survivors. Full article

Background/Objectives: Agarwood has a good neuroprotective effect and is often used to relieve anxiety and treat insomnia. This study compared the similarities and differences in the chromone components of two types of agarwood. It further investigated the absorption and brain distribution characteristics of these components in rats and their neuroprotective effects mediated through anti-neuroinflammatory pathways. Methods: This study confirmed, through ITS2 barcoding and chloroplast genome analysis, that both the ordinary and Qi-Nan agarwood are derived from Aquilaria sinensis. A comparative analysis of chromones in ethanol extracts derived from ordinary and Qi-Nan agarwood, as well as those capable of penetrating the blood-brain barrier in vivo, was conducted using UPLC-Q-TOF-MS. Subsequently, an in vitro neuroinflammatory model was established via lipopolysaccharide (LPS)-stimulated BV-2 cells to evaluate the anti-neuroinflammatory activity of differential chromones. Results: UPLC-Q-TOF-MS characterization revealed the chromone components in the two types of agarwood: A total of 81 chromone compounds were identified in the ethanol extracts of ordinary agarwood (OAE) (20 THPECs, 42 FTPECs, and 19 BI), while 41 were identified in the ethanol extracts of Qi-Nan agarwood (QNE) (11 THPECs and 30 FTPECs). Pharmacokinetic analysis in rats showed that 14 components from OAE (eight THPECs and six FTPECs) penetrated the rat serum, and 10 of these 14 components penetrated the blood–brain barrier (BBB). Twelve FTPECs from QNE penetrated the rat serum, all of which penetrated the BBB. The total peak area of the total ion current (TIC) was calculated for the samples, and the TIC of the serum was compared to that of the brain tissue from the same rat to roughly estimate the ratio. The results demonstrated that the capability of FTPECs to traverse the blood–brain barrier is substantially superior to that of THPECs. Correspondingly, only FTPECs were detected using DESI-MS imaging; no THPECs were detected in rat brain tissue, and DESI-MS imaging localized FTPECs to neuroanatomic regions (cerebral cortex, thalamus, and hippocampus). In vitro neuroinflammatory assays revealed the superior anti-inflammatory efficacy of QNE over OAE (IL-6/TNF-α suppression, p < 0.05), correlating with its FTPEC-rich composition. Conclusions: Structure–activity relationships identified FTPECs as potent inhibitors of pro-inflammatory cytokines, exhibiting enhanced BBB penetration (blood–brain relative abundance > 1). These findings establish FTPECs as prioritized candidates for CNS-targeted therapeutics, with QNE’s pharmacological superiority attributed to its FTPEC dominance and optimized BBB transit capacity. Full article

Frmpd3 (FERM and PDZ Domain Containing 3), a scaffold protein potentially involved in excitatory synaptic function, has not been thoroughly characterized in terms of its expression and functional role in vivo. Here, we investigated the distribution of Frmpd3 in the central nervous system and its potential regulatory role in epilepsy, a neurological disorder characterized by disrupted excitatory–inhibitory balance. The distribution of Frmpd3 throughout the mouse brain was investigated by immunofluorescence. Western blotting was conducted to examine potential alterations in Frmpd3 protein expression in the hippocampus of a pentylenetetrazol (PTZ)-induced chronic epilepsy model. Using stereotaxic techniques, we delivered Frmpd3 siRNA-AAV9 into the hippocampal CA1 region to achieve targeted protein knockdown. Then, the functional consequences of Frmpd3 depletion were assessed through behavioral observations and electrophysiological recordings in PTZ-treated mice. Finally, protein–protein interactions were investigated using immunoprecipitation and Western blot analysis. Immunofluorescence analysis revealed Frmpd3 expression in cortical, hypothalamic, cerebellar, and hippocampal neurons of adult mice. Subcellular localization studies demonstrated predominant distribution of Frmpd3 in the excitatory postsynaptic density (PSD) of hippocampal CA1 neurons, with additional expression in inhibitory neurons. Quantitative analysis showed significantly elevated Frmpd3 protein levels in the hippocampus of PTZ-induced epileptic mice compared to controls. Frmpd3 knockdown in the CA1 region resulted in the following: (1) reduced seizure frequency, (2) prolonged seizure latency, and (3) decreased incidence of PTZ-induced generalized seizures. Local field potential (LFP) recordings demonstrated that seizure amplitude tended to be reduced, and epileptic discharge durations tended to be shorter in Frmpd3-depleted mice compared to controls. Furthermore, we observed decreased membrane expression of the AMPA receptor GluA2 subunit in the hippocampus of Frmpd3 knockdown mice. Molecular interaction studies revealed that Frmpd3 forms complexes with glutamate receptor-interacting protein (GRIP) and GluA2. Our findings identify Frmpd3 as a novel regulatory scaffold protein that modulates epileptic susceptibility through molecular interactions with GRIP and GluA2. The underlying mechanism appears to involve Frmpd3-mediated regulation of GluA2 trafficking from the cytoplasm to the membrane, ultimately enhancing neuronal excitability through increased membrane expression of GluA2-containing AMPA receptors. Full article

Background: The ionotropic glutamate receptor AMPA (AMPAR) mediates fast excitatory synaptic transmission and regulates synaptic strength in various parts of the CNS. Emotional challenges can affect these processes by influencing AMPAR levels and localization via stress hormones, resulting, e.g., in behavioral changes. AMPARs are essential for auditory processing, but their response to stress hormones in the central or peripheral auditory system remains poorly understood. Therefore, this scoping review examines the effects of corticosterone (CORT), a primary stress hormone in rodents, on AMPA receptor levels and localization in the rodent nervous system and considers potential implications for the auditory system. Methods: We systematically searched PubMed, Web of Science, and OVID EMBASE using MeSH terms related to AMPA receptors and corticosterone. Studies were screened based on predefined inclusion criteria, including original research published in English that focused on AMPA receptor subunits (e.g., GluR1-4, GluA1-4, Gria1-4). Of 288 articles screened, 17 met the criteria for final analysis. Results: No reports were found regarding CORT action in the auditory system. Three main experimental models used in the included research were identified: neuronal cultures, isolated tissue cultures, and animal models. Generally, short-term CORT exposure increases AMPAR surface localization and mobility in neuronal cultures, especially in the hippocampus and prefrontal cortex. However, results from animal models were inconsistent due to variations in experimental design and other factors. The isolated tissue study did not provide sufficient data for clear conclusions. Conclusions: Variability in experimental models limits our ability to draw definitive conclusions about the effects of CORT on AMPARs across different regions of the nervous system. The differences in live animal studies highlight the need for standardized methods and reporting. Since AMPARs play a crucial role in auditory processing, CORT-induced changes in neuronal cultures may occur in the auditory system. Further research is needed to explore the specific responses of AMPAR subunits and how stress hormones may influence auditory disorders, which could help identify potential treatment strategies. Full article

Microglia are exceptionally dynamic resident innate immune cells within the central nervous system, existing on a continuum of morphologies and functions throughout their lifespan. They play vital roles in response to injuries and infections, clearing cellular debris, and maintaining neural homeostasis throughout development. Emerging research suggests that microglia are strongly influenced by biological factors, including sex, developmental stage, and their local environment. This review synthesizes findings on sex differences in microglial morphology and function in key brain regions, including the frontal cortex, hippocampus, amygdala, hypothalamus, basal ganglia, and cerebellum, across the lifespan. Where available, we examine how gonadal hormones influence these microglial characteristics. Additionally, we highlight the limitations of relying solely on morphology to infer function and underscore the need for comprehensive, multimodal approaches to guide future research. Ultimately, this review aims to advance the dialogue on these spatiotemporally heterogeneous cells and their implications for sex differences in brain function and vulnerability to neurological and psychiatric disorders. Full article

Alzheimer’s disease (AD) is characterized by complex interactions between neuropathological markers, metabolic dysregulation, and structural brain changes. In this study, we utilized a multimodal approach, combining immunohistochemistry, functional metabolic mapping, and microstructure sensitive diffusion MRI (dMRI) to progressively investigate these interactions in the 5xFAD mouse model of AD. Our analysis revealed age-dependent and region-specific accumulation of key AD markers, including amyloid-beta (Aβ), GFAP, and IBA1, with significant differences observed between the hippocampal formation and upper and lower regions of the cortex by 6 months of age. Functional metabolic mapping validated localized disruptions in energy metabolism, with glucose hypometabolism in the hippocampus and impaired astrocytic metabolism in the cortex. Notably, increased cortical glutaminolysis suggested a shift in microglial metabolism, reflecting an adaptive response to neuroinflammatory processes. While dMRI showed no significant microstructural differences between 5xFAD and wild-type controls, the study highlights the importance of metabolic alterations as critical events in AD pathology. These findings emphasize the need for targeted therapeutic strategies addressing specific metabolic disturbances and underscore the potential of integrating advanced imaging with metabolic and molecular analyses to advance our understanding of AD progression. Full article

In this study, we address the early detection challenges of Alzheimer’s disease (AD) using explainable artificial intelligence (XAI) techniques. AD, characterized by amyloid plaques and tau tangles, leads to cognitive decline and remains hard to diagnose due to genetic and environmental factors. Utilizing deep learning models, we analyzed brain MRI scans from the ADNI database, categorizing them into normal cognition (NC), mild cognitive impairment (MCI), and AD. The ResNet-50 architecture was employed, enhanced by a channel-wise attention mechanism to improve feature extraction. To ensure model transparency, we integrated local interpretable model-agnostic explanations (LIMEs) and gradient-weighted class activation mapping (Grad-CAM), highlighting significant image regions contributing to predictions. Our model achieved 85% accuracy, effectively distinguishing between the classes. The LIME and Grad-CAM visualizations provided insights into the model’s decision-making process, particularly emphasizing changes near the hippocampus for MCI. These XAI methods enhance the interpretability of AI-driven AD diagnosis, fostering trust and aiding clinical decision-making. Our approach demonstrates the potential of combining deep learning with XAI for reliable and transparent medical applications. Full article