Brain aging is driven by progressive failure of neuronal proteostasis, culminating in the accumulation of toxic protein aggregates characteristic of Alzheimer's, Parkinson's, and Huntington's diseases. The AMPK-mTOR-autophagy signaling hub integrates cellular energy status with protein clearance machinery, making it a critical therapeutic node. Caloric restriction mimetics (CRMs), including rapamycin, metformin, resveratrol, and spermidine, exploit this axis by activating AMPK via AMP/ATP modulation and simultaneously suppressing mTORC1 kinase activity. This dual action relieves mTORC1-mediated inhibition of the ULK1 complex, triggering autophagosome nucleation, while sustained mTORC1 suppression promotes TFEB-driven lysosomal biogenesis, collectively restoring autophagic flux. Preclinically, these molecular events enhance clearance of amyloid-β, tau, α-synuclein, and mutant huntingtin and improve mitochondrial quality control via mitophagy. Despite robust mechanistic evidence, clinical translation remains constrained by poor CNS bioavailability, context-dependent autophagic outcomes, and the absence of validated pharmacodynamic biomarkers (e.g., LC3-II turnover, p62 flux) to confirm neuronal target engagement in humans. This review integrates CRM action on the AMPK/mTOR/autophagy axis with both the hallmarks of neuronal aging and disease-specific pathology, providing a molecular framework to guide the rational design of CNS-penetrant formulations, combination strategies, and personalized approaches to modify neurodegeneration.

This review synthesizes recent genetic, molecular, cellular and preclinical evidence on CNTNAP2 function and dysfunction across the neurodevelopmental spectrum from highly penetrant recessive disorder to common autism spectrum disorder risk variation with the focus on human-specific expression patterns, mechanistic convergence on excitatory/inhibitory imbalance and potential translational targets. Biallelic CNTNAP2 loss-of-function defines CASPR2-deficiency disorder (CCD), a stereotyped syndrome of refractory epilepsy, profound language regression, intellectual disability, autistic features and cortical dysplasia that is distinct from the effects of heterozygous variants and common polymorphisms. Single-cell transcriptomics have revealed human-enriched CNTNAP2 expression in anterior frontal and temporal cortices, parvalbumin-positive interneurons and cortico-striato-thalamic circuits, a pattern that contrasts sharply with its rodent cortical expression. At the molecular level, CASPR2 scaffolds juxtaparanodal Kv1 channels through TAG-1/MAGUK interactions and stabilizes interneuron dendrites via CASK, its loss leads to interneuron depletion, impaired perisomatic inhibition and network hypersynchrony in both mouse and human iPSC models. Forebrain organoids derived from homozygous patients demonstrate potentially reversible cortical overgrowth driven by excessive PAX6-positive progenitor proliferation. In preclinical models, early intervention with oxytocin and AMPA receptor modulators has been shown to rescue social deficits and restore excitatory/inhibitory balance in knockout mice. In summary, CNTNAP2 exemplifies a nodal regulator linking axonal excitability, interneuron development and prefrontal network synchrony to a broad spectrum of neurodevelopmental phenotypes. Biallelic loss produces highly penetrant CCD, while common variation modifies autism and language risk. The human-specific expression patterns demand caution in rodent modeling, but circuit-level excitatory/inhibitory biomarkers and targeted interventions represent promising preclinical-stage clinical opportunities that require further validation in genotype-defined cohorts.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that affects an estimated 50 million people worldwide. This remains a significant medical challenge. Despite the availability of numerous therapeutic agents, they are often only partially effective, highlighting the urgent need for the development of more effective next-generation drugs. Triptolide (T10), a key bioactive compound found in traditional Chinese medicine, is renowned for its wide range of pharmacological properties, including promising neuroprotective effects observed in vitro. However, its therapeutic effects and underlying mechanisms in the 5xFAD mouse model, particularly regarding microglial-mediated neuroinflammation, remain incompletely characterized. This study explored the impact of peripherally administered T10 on AD-associated behaviors and neuroinflammation in 5xFAD mice. The findings indicate that a 45-day T10 regimen significantly improved cognitive impairment in mice. Immunohistochemical analyses further demonstrated that T10 treatment markedly decreased Iba1-positive cell density in the CA1 region of the hippocampus and reduced immune and inflammatory responses in this region. Transcriptomic profiling suggests that T10 modulates cognitive function in 5xFAD mice via inflammatory signaling pathways. Taken together, these results suggest that T10 improves learning and cognitive performance and reduces hippocampal inflammatory responses in 5xFAD mice, supporting its further investigation as a potential therapeutic intervention for AD.

Epilepsy is a chronic neurological condition characterised by persistent or recurrent spontaneous seizures caused by aberrant and hyper-synchronisation of neurons. It is one of the leading causes of neurological problems affecting over 50 million people all around the globe, and at present, disease-modifying therapeutic agents are not widely available. This intricate set of molecular processes, including an imbalance between excitatory glutamatergic and inhibitory GABAergic neurotransmission, neuroinflammation, long-term oxidative stress, and activity-induced transcriptional reprogramming, is the genesis of epilepsy. The findings highlight the role of epigenetic regulators in linking repeated neuronal activity to long-term changes in gene expression that stabilise the hyperexcitable neural system. Recently, coactivator-associated arginine methyltransferase-1, a type 1 protein arginine methyltransferase, has gained attention as a core activity-responsive epigenetic enzyme that integrates chromatin remodelling and neuronal signaling. CARM1 is a histone H3 and non-histone asymmetric dimethyltransferase that orchestrates transcriptional programs implicated in maintaining chromatin accessibility, synaptic plasticity, neuronal excitability, and inflammatory mediator expression. The dysregulated activity of CARM1 has been implicated in increased glutamatergic signaling, diminished GABAergic inhibition, persistent neuronal hyperexcitability, and heightened microglial and astrocytic inflammatory responses, all of which play key roles in epileptogenic remodelling of connectivity. The review provides an overall synthesis of current mechanistic understanding of CARM1's functions in epilepsy, with specific attention to the mechanisms by which CARM1 regulates the excitatory-inhibitory balance, neuroinflammatory signals, and activity-dependent transcriptional plasticity. The manuscript also discusses the preclinical evidence, translational challenges, and future experimental requirements for evaluating CARM1 as a potential therapeutic target in epilepsy.

The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence αSyn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.

HUWE1 (HECT, UBA, and WWE domain-containing protein 1) is an X-linked E3 ubiquitin ligase that regulates a broad range of substrates through both degradative and non-degradative ubiquitination. The essential role of HUWE1 is underscored by the neonatal lethality of Huwe1 knockout mice. Although HUWE1 has been extensively studied in cancer and neurodevelopment, its functions in brain aging and neurodegeneration remain poorly understood. Here, we used cross-linking-assisted immunoprecipitation coupled with mass spectrometry to characterize HUWE1 interactomes in 26-month-old wild-type and Tg-SwDI mouse brains. HUWE1 interactomes were enriched for proteins involved in gene expression, translation, synaptic signaling, and nucleic acid metabolism. HUWE1-associated protein complexes contained an extensive network of nucleic acid-binding proteins, including the G-quadruplex-associated helicases DDX5, DDX3X, DDX3Y, and DDX17, the nucleic acid-binding proteins nucleolin and FUS, and the DNA topology regulator TOP2B. These interactomes exhibited both disease- and sex-specific organization. Independent biochemical validation confirmed the association between HUWE1-containing complexes and the G-quadruplex helicase DDX5. In addition, APOE was uniquely detected in Tg-SwDI HUWE1 interactomes and was more abundant in females than in males, suggesting a disease- and sex-specific association between HUWE1-containing complexes and APOE. Taken together, these findings identify HUWE1 as a component of sex-specific nucleic acid-binding protein networks in the aging brain and provide new insights into its potential roles in neurodegeneration.

Neuropsychiatric disorders have a high global health impact; however, the molecular basis of these disorders is still not fully understood due to the intricate complexity of neuronal homeostasis. In this review article, we have highlighted an emerging paradigm that places nuclear calcium signaling at the apex of cellular metabolism by bridging synaptic functions and mitochondrial proteostasis. We have highlighted how cytosolic and nucleoplasmic Ca[2+] transients orchestrate a "transcription-to-translation" process that is crucial for the expression of mitochondrial proteasomal and biogenesis-related genes. In this review article, we have critically analyzed pathways, including ER-IP3R coupling, MCU-mediated Ca[2+] uptake, and the PINK1-Parkin pathway, that contribute to a "synaptic energy gap" due to bioenergetic failure and oxidative stress arising from aberrant calcium homeostasis. One of the major highlights of this review article is our critical examination of the CaMKII-CREB-BDNF pathway, which plays a crucial role in mitochondrial biogenesis in response to alterations in energy homeostasis. We have explored beyond the conventional by critically analyzing how modern psychotropic agents such as Ketamine, Lithium, and Valproate effectively reboot these pathways to overcome bioenergetic failure. Through the integration of the latest advances in structural biology with clinical psychiatry, this review creates a framework where mitochondrial pathology is not only a consequence, but rather a cause, of psychiatric disorders. Ultimately, this review creates a framework for developing next-generation, molecularly targeted therapeutics capable of healing the energetic defects that underlie the human mind.

Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuronal loss, and sustained neuroinflammation. In recent years, pyroptosis, a gasdermin-mediated form of inflammatory programmed cell death, has been recognized as a potential mechanism linking innate immune activation to neurodegenerative injury. This review summarizes the major molecular pathways of pyroptosis, including the canonical inflammasome-caspase-1-GSDMD pathway, the noncanonical caspase-4/5/11-GSDMD pathway, and alternative pathways involving caspase-3/GSDME and caspase-8, with a focus on their roles in the initiation, amplification, and propagation of neuroinflammation in AD. Current evidence suggests that AD-related stimuli, including Aβ aggregation, tau pathology, mitochondrial dysfunction, oxidative stress, and lysosomal damage, can induce inflammasome activation, gasdermin cleavage, and inflammatory mediator release, thereby sustaining chronic neuroinflammation. Concurrently, microglia, neurons, astrocytes, and oligodendrocytes may exhibit varying degrees of pyroptosis-related responses, contributing to impaired Aβ clearance, neuronal injury, glial dysfunction, and myelin pathology, respectively. This review further summarizes potential therapeutic strategies targeting the NLRP3 inflammasome, caspases, gasdermins, natural bioactive compounds, and the gut-brain axis. Overall, pyroptosis provides a novel framework for understanding the interplay between neuroinflammation and neurodegeneration in AD; however, its cell-type-specific roles, stage-dependent effects, and translational potential remain to be fully elucidated.

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.