Mitochondrial dysfunction is a cardinal, causative, and convergent hallmark in both Alzheimer's disease (AD) and Parkinson's disease (PD). However, therapeutics that target the process of mitophagy, the selective removal of damaged mitochondria, are relatively undeveloped. Prior work has largely centered around post-translational modifications of the PINK1-Parkin signaling pathway while ignoring the key need for sustained protein synthesis of Parkin. In this review, we explore an innovative transcriptional circuit involving the gut microbiome, AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and mitophagy: gut-derived metabolites, such as Urolithin A (UA), activate AMPK and SIRT1, both of which converge to deacetylate and phosphorylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The transcription of the mitophagy protein, Parkin, is then driven by activation of PGC-1α. This UA/AMPK/SIRT1/PGC-1α/Parkin/mitophagy pathway is disrupted in multiple layers in AD and PD; this includes impaired gut function, lowering the level of UA produced in the body, proteinopathy leading to reduced PGC-1α activity, and decreased transcription of Parkin. Therapeutic targets of these various nodes include UA, PGC-1α activator ZLN005, and SIRT1 activators, such as resveratrol or nicotinamide riboside. By shifting the paradigm from post-translational activation to transcriptional restoration of Parkin, this gut-brain metabolic axis offers a unifying, testable, and therapeutically tractable framework for mitigating mitophagy failure in AD and PD.

Prion protein (PrP) lowering is a validated therapeutic hypothesis in prion disease. To identify small molecules that reduce PrP levels, we performed phenotypic screening in cultured cells. To prioritize PrP specificity in our primary screen, we generated mouse N2a cells stably expressing GFP and used high content imaging analysis to select compounds that lowered PrP without affecting GFP signal or cell viability. Screening a curated library of 3492 compounds with annotated mechanisms of action identified two small molecules, EYH (PubChem CID: 71678945) and LCZ (PubChem CID: 24970350), that selectively and dose-dependently lowered PrP. Proteomics on whole cell lysates identified PrP as the #1 or #2 most potently downregulated out of 8722 proteins detected. Both compounds minimally affected Prnp mRNA, reduced expression of exogenously transfected PrP, and remained potent in non-dividing primary cells, consistent with a post-translational mechanism. Co-treatment with the proteasome inhibitor MG132 yielded accumulation of unglycosylated PrP, demonstrating proteasome clearance of PrP. However, both compounds showed limited or no activity in human cell lines, and failed to reduce PrP in vivo after 14 days of treatment. These findings highlight the challenges associated with mechanism-agnostic phenotypic screening for PrP-lowering compounds and support prioritizing compounds with known mechanisms of action.

Apolipoprotein E, a glycoprotein, is one of the strongest genetic risk factors for late-onset Alzheimer's disease. APOE is involved in the transport and metabolism of cholesterol, phospholipids and other lipids, synaptic function and neuroinflammation in the CNS. One of the key functions of APOE is to bind and deliver newly synthesized cholesterol and lipids to neurons through receptor-mediated endocytosis (LDLR, LRP1, VLDLR, APOER2). The APOE gene exists in three common isoforms: APOE2, APOE3, and APOE4, with distinct structural and functional properties. The three isoforms of APOE vary in their potential to bind and transport lipids and cholesterol, receptor affinity and clearance of Aβ. Among the three isoforms, APOE4 is one of the strongest risk factors for late-onset Alzheimer's disease, while APOE2 exerts a protective role highlighting the functional divergence among isoforms in CNS physiology. The functions of APOE are exerted through binding of APOE with members of the low-density lipoprotein receptor (LDLR) family, including LDLR, LRP1, VLDLR, and APOER2. So, approaches that potentiate the protective effects of APOE, like APOE mimetics, ABCA1 agonists, targeting APOE receptors like LDLR, LRP1, APOER2, and TREM2, might offer significant therapeutic benefits in Alzheimer's disease.

Bone marrow-derived mesenchymal stromal cells (BMSCs) have been shown to enhance regeneration and repair, even in challenging neurological conditions such as spinal cord injury (SCI). However, their clinical application for SCI remains inconsistent, likely due to variability in therapeutic outcomes. In our laboratory experiments, we observed similar inconsistencies, including instances where the presence of BMSCs compromised the survival of co-cultured neurons subjected to oxidative stress in vitro. The present study was carried out to find answers for such paradoxical effects caused by BMSCs using an in vitro model involving primary cultured neurons and BMSCs. Both neurons and BMSCs were found to upregulate brain-derived neurotrophic factor (BDNF) production under oxidative stress. To simulate BMSC-mediated release, we introduced exogenous mature BDNF (mBDNF) to stressed neurons in cultures, which unexpectedly led to apoptosis. Observations suggest the possibility of mBDNF-p75 neurotrophin receptor (p75NTR) mediated cell death signaling. Notably, administration of a p75NTR inhibitor (LM11A-31, a small molecule) partially alleviated these detrimental effects. Given the growing interest in BMSC-based therapies, these findings underscore concerns regarding the variability of their effects and the potential for unintended neurotoxicity. Addressing these inconsistencies through further studies will be critical to ensuring the safety and efficacy of BMSC applications in clinical settings. In this regard, concomitant inhibition of p75NTR using small molecules such as LM11A-31 may have potential to avoid contradictory effects of BMSC transplantations caused by unpredictable release of excess BDNF in the transplanted site.

Sleep is a vital physiological process essential for maintaining neural homeostasis, cognitive function, behavior, and health. Sleep deprivation (SD) is an increasing public health concern, largely driven by modern lifestyles and occupational demands. Research shows that SD induces oxidative stress and neuroinflammation, leading to structural changes in neurons, particularly in hippocampus, a brain region critical for learning and memory. Long-term SD has been associated with an increased risk of neurodegenerative disorders, metabolic disorders, and cardiovascular diseases. Therefore, understanding the type and extent of sleep loss and its impact on neural and overall health is essential for managing individuals affected by SD. In this review, we summarize the current literature on SD-induced changes in the brain, focusing on: (i) methods used to induce SD, (ii) SD-induced oxidative stress and neuroinflammatory alterations in the brain, (iii) effects of SD on dendritic arborization in hippocampal neurons, (iv) neuronal loss in hippocampus and other brain region, (v) impact of SD on spatial memory and behavior, and (vi) the efficacy of sleep recovery in reversing SD-induced changes. The literature shows that both acute and chronic sleep deprivation (CSD) increased oxidative stress, decreased dendritic arborization, increased neuronal loss, induced anxiety, and impaired spatial memory. While sleep recovery mitigates the damage caused by SD, full reversal depends on type of SD and duration of recovery, especially the CSD induced damage is not fully reversed. Overall, the evidence underscores the importance of understanding the nature of sleep loss and its neural impacts for developing effective strategies to manage SD.

Chronic stress is a major risk factor for psychiatric and neurological disorders, operating through interconnected molecular cascades that link neuroendocrine dysfunction to synaptic pathology. This review mechanistically examines how stress-induced hypothalamic-pituitary-adrenal (HPA) axis hyperactivation sustains glucocorticoid release, driving microglial activation and astrocytic reactivity toward pro-inflammatory phenotypes characterized by immunometabolic reprogramming. Key inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and quinolinic acid (QUIN) derived from the upregulated kynurenine pathway (KP)- impair glutamate homeostasis by compromising astrocytic reuptake and promoting excitotoxic extrasynaptic N-methyl-d-aspartate receptor (NMDAR) signaling. These pathological alterations disrupt synaptic plasticity through modified NMDAR subunit composition, impaired long-term potentiation (LTP), and complement cascade-mediated synaptic pruning, establishing a self-perpetuating cycle of vulnerability particularly within the hippocampus and prefrontal cortex. Consequently, by elucidating these interconnected pathways reveals promising therapeutic targets, including microglial phenotype modulators, NMDAR-specific interventions, and integrated pharmacological and non-pharmacological strategies aimed at restoring synaptic homeostasis and circuit function. Ultimately, this review maps these biological pathways to outline protective interventions against the physical damage of chronic stress, offering a roadmap for new treatments to restore healthy neural connections and brain function.

Diseases of the central nervous system (CNS) often include neuronal damage. This study examined proteins crucial to apoptosis and neuronal signalling for identifying causes of neuronal dysfunction in two animal models: Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) and ethidium bromide (EtBr)-induced focal spinal cord injury. Transcriptomic analysis revealed increased levels of pro-apoptotic molecules including Caspase 8 (Casp8) and Cathepsin B (CTSB), but no significant changes in synaptic proteins including synaptophysin, synaptosomal-associated protein of 25 kDa (SNAP25) and postsynaptic density protein of 95 kDa (PSD95). Immunohistochemistry showed increased levels of pro-apoptotic proteins Casp8 and CTSB in the grey matter of TMEV-IDD but reduced levels of these proteins following EtBr injection. Synaptophysin, a marker for neuronal signalling, was reduced in the grey matter in both models. Drebrin, a protein related to neuronal plasticity, was significantly reduced in the grey matter of EtBr-injected mice, but increased in the white matter of TMEV-infected mice. Summarized, the upregulation of pro-apoptotic molecules in TMEV-IDD without apoptotic neurons suggests an incomplete apoptosis, while their reduction in EtBr-injected mice may indicate a reversible neuronal damage. The reduction of synaptophysin in both models indicates a possible impairment of synaptic transmission while the reduction of Drebrin in EtBr-injected mice may be associated with a reduced synaptic plasticity.

Mutations in the EFHC1 (EF-hand domain containing 1) gene, which encodes myoclonin1, a homolog of the Chlamydomonas axonemal protein Rib72, have been identified in patients with epilepsies including juvenile myoclonic epilepsy (JME). Myoclonin1 is expressed in choroid plexus epithelial cells during fetal development and in motile cilia of ependymal cells lining brain ventricles as well as in tracheal cilia and sperm flagella during postnatal stages. We previously reported that systemic Efhc1 deficiency in mice causes spontaneous myoclonus, increased susceptibility to the chemoconvulsant pentylenetetrazol (PTZ), and enlargement of brain ventricles. In the present study, we show that mice with selective deletion of myoclonin1 in choroid plexus and ependymal cells, generated by crossing newly developed floxed-Efhc1 mice with FoxJ1 (forkhead box J1)-Cre driver mice, exhibit increased susceptibility to PTZ-induced seizures in adult heterozygous mutants and enlarged brain ventricles in homozygous mutants, while neither heterozygous nor homozygous mutants display spontaneous myoclonus. These findings suggest that myoclonin1 haploinsufficiency in cells bearing motile cilia partially reproduces the epileptic phenotypes observed in mice with systemic Efhc1 deficiency and contributes to the pathophysiology of epilepsies associated with EFHC1 mutations.

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder that results from loss-of-function (LOF) mutations in the Transcription Factor 4 (TCF4) gene. PTHS closely resembles Rett syndrome (RTT), another neurodevelopmental disorder caused by mutations in the gene encoding Methyl CpG Binding Protein 2 (MECP2). We have recently shown that increasing MeCP2 levels, either genetically or via a viral vector approach, normalizes reciprocal behavioral phenotypes observed in Tcf4[+/-] and MECP2-overexpressing animals; in the current manuscript, we show that behavioral rescue also extends to a contextual fear learning task. Tcf4 heterozygous and knock-in mouse lines exhibit consistent myelination abnormalities, with an arrest of oligodendrocytes (OLs) at an immature stage. To address the hypothesis that correction of myelination defects is the potential mechanism underlying the behavioral rescue induced by MeCP2 increases in Tcf4[+/-] animals, we performed RNA-sequencing and protein expression studies. These experiments revealed that increasing MeCP2 does not dramatically affect the transcriptional profile induced by heterozygosity at Tcf4, as well as vice-versa, and subsequent molecular experiments suggest that OL gene expression and molecular phenotypes in Tcf4[+/-] animals are unchanged in the presence of an MECP2 transgene. However, we also find increased levels of Olig2 and Gfap co-expressing cells in Tcf4[+/-] mice in the presence of the MECP2 transgene, as well as the presence of cells with astrocytic morphology in the brains of these animals, suggesting a potential interplay of MeCP2 and TCF4 in astrocyte development.

Status epilepticus (SE) is a prolonged seizure state that can induce lasting hippocampal damage and promote the development of spontaneous seizures and cognitive deficits. The severity and duration of SE affect long-term outcomes; however, many studies rely on behavioral assessments such as the Racine scale, which may miss subclinical or non-convulsive seizures and leave the molecular effects of mild SE unclear. Here, we examined whether behavioral seizure severity in the pilocarpine rat model of acquired epilepsy correlates with distinct hippocampal proteomic changes. Adult male rats were classified as control, mild SE, or severe SE following pilocarpine-induced seizures, and hippocampal tissue was analyzed using mass spectrometry-based proteomics. Partial least squares discriminant analysis revealed distinct proteomic signatures across groups. Severe SE was associated with widespread changes (129 differentially expressed proteins [DEPs]) involving synaptic structure, RNA regulation, and metabolism, whereas mild SE showed fewer alterations (81 DEPs) related primarily to synaptic organization and endocytosis. Comparison of severe and mild SE identified 76 DEPs enriched in pathways linked to synaptic plasticity and neurodegeneration, with 23 proteins exhibiting a stepwise expression pattern across seizure severities. Glial and inflammatory proteins emerged as candidate markers of seizure burden. These findings demonstrate that behavioral seizure severity aligns with specific hippocampal proteomic profiles and that even lower-severity SE induces molecular changes relevant to epileptogenic progression.

Cerebral ischemia (CI) triggers a cascade of cellular communication disruptions, with chemokines serving as key mediators of neuroinflammation and blood-brain barrier (BBB) dysfunction. This review outlines current knowledge on the specific functions of chemokines and their receptors in CI development, emphasizing their potential as therapeutic targets. It details the mechanisms of chemokine release, including the role of extracellular vesicles (EVs) from various glial and neuronal cells, and examines how post-translational modifications (PTMs) influence chemokine and receptor activity. The review also explores signaling pathways such as NF-κB, p38 MAPK, PI3K/AKT, and RhoA/ROCK, which are central to chemokine responses. A significant focus is on the bidirectional communication between neurons and glia, highlighting dynamic shifts in chemokine signaling from acute injury to chronic repair. By targeting this network-using receptor antagonists and modulating chemokine release-we aim to discover new therapeutic strategies. This comprehensive framework enhances understanding of the spatiotemporal and molecular intricacies of chemokine signaling in CI, guiding the development of precise interventions to support neuroprotection and functional recovery.