Thirupathirao Vishnumukkala

Mitochondria are critical for bioenergetics, calcium and redox homeostasis, and apoptosis in neurons. Neurons are especially susceptible to mitochondrial malfunction since they are terminally differentiated and have extraordinary energy requirements. Mechanisms such as defective oxidative phosphorylation, altered fission-fusion dynamics, defective mitophagy, impaired axonal transport and excessive reactive oxygen species (ROS) generation are increasingly appreciated as important mechanisms in major neurodegenerative diseases (NDDs) like Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). The review discusses the structure and function of mitochondria with emphasis on oxidative phosphorylation, ROS and reactive nitrogen species (RNS) signalling, calcium-mediated excitotoxicity, lipid metabolism, and apoptotic and non-apoptotic cell-death mechanisms including necroptosis, ferroptosis, pyroptosis and parthanatos. In particular, disease-specific processes are highlighted, such as impaired mitophagy by amyloid β/tau in AD, PTEN-induced kinase 1 (PINK1)/Parkin dysfunction and complex I inhibition in PD, Superoxide Dismutase 1 (SOD1)/C9orf72-associated mitochondrial defects in ALS, and bioenergetic dysfunction by mutant huntingtin in HD. Therapeutic approaches include mitochondria-targeted antioxidants, fusion and biogenesis enhancers, fission inhibitors, inflammasome modulators, Mitochondrial Permeability Transition Pore (mPTP) inhibitors and gene therapy. Also highlighted are recent advancements such as Ubiquitin-Specific Peptidase 30 (USP30) inhibition, intercellular mitochondrial transfer and regulatory approval of a mitochondria-targeted peptide, together with evidence supporting causality and hurdles underpinning clinical translation. Graded against human-genetic, patient-tissue and model-based evidence, mitochondrial dysfunction is best supported as a primary driver in PD and genetic ALS, and as an early amplifier of proteinopathic or mutant-huntingtin toxicity in sporadic AD and HD.

Alzheimer’s disease (AD) is a complex disease that involves systemic, vascular, and metabolic components affecting the brain, in addition to amyloid-beta (Aβ) and tau pathology. The microbiota–gut–brain axis, a bidirectional communication network between the gastrointestinal tract and the central nervous system, involving neural, immune, endocrine, and metabolic pathways, has arisen as a mechanistically plausible and clinically relevant contributor to AD pathogenesis among these systemic contributors. This review integrates information from human observational research, preclinical transgenic and germ-free models, and clinical trials to assess how gut dysbiosis, intestinal barrier dysfunction, and microbial metabolites converge on amyloidogenic and tau-associated pathways. In preclinical models, disruption of intestinal barrier integrity is proposed to allow translocation of lipopolysaccharide and bacterial amyloids into the systemic circulation, activating Toll-like receptor and NLRP3 inflammasome signaling that may prime microglia and astrocytes towards a chronic neuroinflammatory state. Further, dysbiosis-mediated changes in short-chain fatty acid, tryptophan–kynurenine, and bile acid metabolism may influence amyloid precursor protein processing, microglial clearance capability, and tau phosphorylation. Preclinical germ-free and fecal-transfer investigations provide fundamental evidence for these pathways in rodent models, while human case–control and Mendelian randomization data indicate converging yet diverse associations that have not yet established underlying directionality in human disease. Therapeutic modulation of the axis has shown promising early phase and observational signals using probiotics, synbiotics, dietary pattern interventions, fecal microbiota transplantation and pharmacological targeting of the GLP-1 pathway; however, the phase 3 EVOKE and EVOKE+ trials of oral semaglutide did not meet their primary cognitive endpoint, and heterogeneity of trials, short follow-up, and inconsistent reporting of biomarkers currently preclude definitive conclusions. We conclude that the microbiota-gut–brain axis is a biologically plausible and therapeutically tractable component of AD pathophysiology, but translation from mechanistic plausibility to clinical utility will depend upon longitudinal, biomarker-anchored and adequately powered interventional trials in genetically and microbiologically diverse populations. Because diet is among the most readily modifiable determinants of gut microbiome composition and function, this review prioritizes dietary patterns, prebiotic fibers, and probiotic or synbiotic supplementation as practical strategies for investigating the microbiota–gut–brain axis in AD. Their disease-modifying efficacy remains unproven; therefore, mechanistic and pharmacological approaches are discussed as complementary avenues for informing future research.

Background: Atrial septal defect (ASD) is a congenital cardiac abnormality, representing roughly 10% of all congenital heart problems. The ostium secundum type is the truly familiar form, characterised by a deficit in the fossa ovalis. A significant proportion of instances, sometimes diagnosed in childhood, remain asymptomatic and undiscovered for the whole of a patient's life. Case Presentation: An incidental discovery of a multi-fenestrated ostium secundum-type atrial septal defect was made during routine cadaveric dissection of a 60-year-old male cadaver. Five distinct fenestrations were observed within and around the fossa ovalis area of the interatrial septum, located in its superior, central, and inferior segments a configuration characteristic of the 'swiss-cheese' septal variety. The fossa ovalis boundary was discernible as a fibrous ring, however the floor and adjacent septum secundum tissue were significantly perforated. This individual has no recorded history of congenital heart disease. Conclusion: This case highlights the clinical and anatomical importance of multi-fenestrated ostium secundum atrial septal defect, a morphological variety characterised by numerous distinct perforations instead of the anticipated singular central opening. The observed 'swiss-cheese' pattern has significant implications during surgical intervention, since it frequently prevents conventional single-device transcatheter closure and may require surgical patch repair. This case underscores the significance of cadaveric dissection in revealing intricate congenital abnormalities that may remain asymptomatic during a affected population life. KEYWORDS: Atrial septal defect. Ostium secundum, multi-fenestrated atrial septal defect, Cadaveric dissection.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and a leading cause of dementia worldwide, yet effective disease-modifying therapies remain elusive. Rodent models have been indispensable for elucidating key pathological mechanisms, including amyloid-beta (Aβ) deposition, tau pathology, neuroinflammation, and synaptic dysfunction. However, despite decades of preclinical success, the translation of therapeutic findings from rodent studies to clinical efficacy in humans has been largely unsuccessful, highlighting critical limitations in current modelling approaches. This narrative review provides a comprehensive and critical evaluation of rodent models of AD, encompassing transgenic, chemically induced, metabolic, inflammatory, and lesion-based paradigms. Rather than presenting these models in isolation, we propose a systems-level framework that categorizes them based on their ability to recapitulate distinct domains of AD pathology, including genetic, environmental, and systemic contributors. By synthesising existing research, highlighting critical gaps, and proposing a tiered minimum-criteria framework for the development of next-generation models, we offer a definitive operational roadmap instead of merely a list of deficiencies. We highlight that most existing models predominantly reflect familial and reductionist aspects of the disease, while failing to capture the complexity of sporadic AD, aging processes, vascular dysfunction, and whole-body interactions. Importantly, we emphasize emerging dimensions that are underrepresented in current rodent models, including glymphatic dysfunction, cerebral small vessel disease, and the microbiota–gut–brain axis, all of which play crucial roles in AD pathogenesis. We further discuss how integrating these factors into next-generation models may improve translational relevance and therapeutic predictability. By synthesizing current evidence and identifying key gaps, we provide a strategic roadmap for the development of more physiologically relevant and translationally robust rodent models. Advancing toward integrative, systems-based approaches will be essential for bridging the persistent gap between preclinical discoveries and clinical success in AD.

Alzheimer’s disease (AD) is increasingly recognized as a disorder of dysregulated neuroimmune connectivity rather than isolated proteinopathy. The immuno-glial connectome, the dynamic interplay between microglia, astrocytes, and peripheral immune systems, constitutes a central driver of disease initiation and progression. Emerging single-cell and spatial transcriptomic studies reveal heterogeneous glial subpopulations with context-dependent transcriptional programs governed by TREM2–APOE, NF-κB, JAK/STAT, and NLRP3 inflammasome signaling. These networks converge to sustain chronic inflammation, impair amyloid-β clearance, and accelerate tau pathology. Complement dysregulation (C1q–C3 axis) further promotes aberrant synaptic pruning, while cytokine feedback loops involving IL-1β, TNF-α, and IFN-γ amplify neurotoxicity. Beyond the brain, peripheral immune cells, monocytes, macrophages, T and B lymphocytes, and neutrophils breach the compromised blood–brain barrier (BBB), perpetuating inflammatory cascades. Parallelly, gut dysbiosis and microbial metabolites modulate microglial reactivity via the gut–brain axis (GBA), linking systemic inflammation to central immune activation. Recent advances in plasma and cerebrospinal biomarkers (GFAP, sTREM2, YKL-40, and neurofilament light chain) enable in vivo tracking of neuroinflammatory dynamics, bridging mechanistic research with clinical translation. Therapeutic strategies targeting the immuno-glial interface, including selective NLRP3 inhibitors, TREM2 agonists, anti-cytokine biologics, and microbiome modulation, are reshaping the therapeutic landscape. Framed through the concept of an immune–glial connectome, this review synthesizes how coordinated interactions among microglia, astrocytes, and peripheral immune cells converge to drive synaptic dysfunction, circuit-level disintegration, and cognitive decline in neurodegenerative disease, particularly in AD. Graphical Abstract An immuno-glial network in AD, where central glia, peripheral immune cells, and the gut–brain axis interact through cytokines, oxidative stress, and barrier dysfunction. These interrelated pathways amplify inflammation via NF-κB, JAK/STAT, and NLRP3 signaling, linking immune dysregulation to neurodegeneration.

Despite decades of research, Alzheimer’s disease (AD) remains without a curative therapy. While amyloid- and tau-centered approaches have dominated the field, failures of monotherapeutic strategies underscore the need for a broader system-level understanding. Here, this review critically revisits the principal hypotheses of AD pathogenesis, including the amyloid cascade, tauopathy, neuroinflammation, cholinergic dysfunction, oxidative and mitochondrial stress, metal dyshomeostasis, autophagy–lysosomal failure, genetic susceptibility, and infectious triggers. This review synthesizes molecular and cellular evidence from human genetics, neuropathology, and experimental models, correcting common misconceptions and emphasizing interactions between pathways. Neuroinflammation is increasingly recognized as a central hub linking amyloid, tau, and vascular factors, while mitochondrial and lysosomal dysfunctions emerge as amplifiers of proteotoxic stress. Genetic studies highlight apolipoprotein-E ε4 (APOE ε4) as the strongest common risk allele, but also implicate genes involved in endosomal trafficking, lipid metabolism, and immune regulation. Taken together, AD is best understood as a multi-hit disorder in which converging processes, rather than a single driver, dictate disease initiation and progression. This narrative review proposes a systems neurobiology framework that integrates these mechanisms and identifies key points of convergence amenable to therapeutic targeting and biomarker development. Finally, this reappraisal aims to inform future research directions and guide the rational design of multi-target interventions.

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, multiple sclerosis, and amyotrophic lateral sclerosis share converging mechanisms of neuronal dysfunction, including protein aggregation, oxidative stress, and chronic neuroinflammation. Glial cells, once considered passive supporters, are now recognized as central drivers of these processes, offering both pathogenic triggers and therapeutic opportunities. Yet, despite compelling preclinical evidence, the translation of glial-targeted therapies into clinical success has been limited. This review provides a critical synthesis of current knowledge by examining therapeutic strategies through the lens of their translational challenges and failures. This narrative review highlights how interspecies variability of glial phenotypes, shifting neuroprotective versus neurotoxic states, limited biomarker stratification, and delivery barriers have constrained trials, such as anti-triggering receptor expressed on myeloid cells 2 (anti-TREM2) antibodies in AD and glial cell line-derived neurotrophic factor (GDNF) in PD. By analyzing these obstacles across major neurodegenerative disorders, this review argue that the next stage of glial medicine requires precision approaches that integrate stage-specific phenotyping, biomarker-guided patient selection, and innovative delivery platforms. Understanding not only what has been tried but why translation has stalled is essential to chart a roadmap for effective, disease-modifying glial therapies in the aging brain.

Centella asiatica (C. asiatica) has attracted significant scientific interest due to its extensive medicinal properties and long-established use in traditional medicine. This review synthesizes recent advances in the technological exploitation of C. asiatica, covering the extraction of bioactive constituents to product development. Modern extraction techniques such as supercritical fluid extraction (SFE) and microwave-assisted extraction (MAE) have substantially improved the yield, selectivity, and preservation of key phytochemicals, particularly triterpenoids, saponins, and flavonoids. These compounds are now routinely characterized using advanced analytical platforms, ensuring product quality, consistency, and standardization. Moreover, the use of innovative formulation technologies and advanced delivery systems has facilitated the development of C. asiatica-based products tailored for various therapeutic areas, including pharmaceuticals, nutraceuticals, and cosmeceuticals targeting neuroprotection, wound healing, skin aging, and stress modulation. Alongside these developments, stringent quality control protocols, toxicological evaluations, and adherence to evolving regulatory standards enhance the safety and efficacy of C. asiatica-derived interventions. This review highlights the integration of traditional knowledge with modern science across the domains of extraction, analysis, formulation, and regulation. It serves as a comprehensive resource for researchers, formulators, and regulatory stakeholders aiming to develop high-quality, evidence-based C. asiatica products with improved bioavailability and therapeutic value.