Reactive astrocytes play a central role in shaping the post-injury microenvironment after spinal cord injury (SCI), yet the molecular mechanisms governing their proliferative expansion and contribution to scar architecture remain incompletely defined. Conditional deletion of CRMP4 in astrocytes significantly reduced astrocyte proliferation, altered scar organization, and attenuated the inflammatory milieu surrounding the lesion, including reduced microglial activation. These changes were accompanied by significantly improved locomotor recovery, as assessed by the Basso Mouse Scale (BMS) locomotor rating scale, indicating enhanced functional restoration after SCI. Our findings suggest that CRMP4 promotes the expansion of reactive astrocyte subsets that shape the inhibitory niche surrounding the lesion core, thereby restricting axonal regeneration and limiting functional recovery after SCI. Single-cell RNA sequencing (scRNA-seq) analysis of a public dataset revealed that Crmp4 expression is enriched in proliferative, progenitor-like astrocyte subpopulations that contribute to scar formation, including subclusters corresponding to the G2/M phases of the cell cycle. Together, this study identifies astrocytic CRMP4 as a key molecular determinant of reactive astrocyte dynamics and scar architecture after SCI, providing new insight into cell-type-specific regulation of glial responses in central nervous system injury.
Alzheimer's disease (AD) is now recognized as a biologically heterogeneous syndrome in which amyloid-β pathology, Tau-related alterations, and neuroinflammation are key interconnected processes. Microglia, astrocytes, oligodendrocytes, complement, inflammasomes, neurovascular cells, and peripheral immunity are implicated as both adaptive and disease-promoting contributors to the pathophysiology of AD. Here, we highlight mechanisms by which innate immunity and peripheral immune cells influence amyloid β-peptide metabolism, Tau pathophysiology, excitatory synaptic function, oxidative stress response, blood-brain barrier integrity, and systemic inflammation in the context of Alzheimer's disease. A particular focus is made on the role of TREM2-related microglial function and the NLRP3 inflammasome, complement-mediated synaptic pruning, astrocyte crosstalk, and the limitations of the M1/M2 and A1/A2 concepts. A distinction is made between biomarkers of core AD pathophysiology and those specific to neuroinflammation and neurodegeneration. An emphasis is placed on the clinical utility of plasma p-tau217 in combination with Aβ42/Aβ40, GFAP, NfL, sTREM2, YKL-40, and neuroinflammation imaging. With respect to therapeutics, an effort is made to focus on the need to harness desirable inflammatory pathways while specifically targeting deleterious processes rather than adopting an overarching anti-inflammatory approach. Single-cell, spatial, multi-omics, and biomarker-driven approaches may enable patient stratification based on underlying pathophysiology, allowing for stage-specific combination therapeutic strategies. Overall, studies presented in this review highlight a precision-neuroimmunology concept in which neuroinflammatory processes are both triggers and effectors of disease pathology and can be selectively modulated for clinical benefit.
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.
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 Ca2+ 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 Ca2+ 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.
