Park A, et al. J Korean Med Sci. 2021 Sep;36(40):e261. https://doi.org/10.3346/jkms.2021.36.e261

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which amyloid β accumulation, tau pathology, chronic neuroinflammation, and metabolic stress converge to drive synaptic dysfunction and neuronal loss. Rather than resulting from a single mechanism, increasing evidence indicates that neurodegeneration in AD is mediated by the coordinated activation of multiple regulated cell death pathways. These pathways include apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death, each characterized by distinct molecular mediators and execution programs. Evidence from human brain tissues, animal models, and in vitro systems demonstrates that core pathological drivers such as amyloid β and tau pathology, oxidative stress, and sustained neuroinflammation engage these death pathways in a spatially, temporally, and cell-type-dependent manner across neurons and glial populations. In this review, we synthesize the current knowledge on regulated cell death mechanisms in AD, emphasizing their molecular signatures, cellular specificity, and stage-dependent involvement, together with recent advances in immunohistochemical, imaging, and biofluid-based approaches for detecting neuronal death. By integrating evidence across molecular, cellular, and system levels, this review positions regulated cell death as a unifying framework for understanding neurodegeneration and developing pathway-specific biomarkers and combinatorial neuroprotective strategies.

Background and Objectives: Therapeutic hypothermia (TH) shows promise as an approach with neuroprotective effects, capable of reducing secondary brain damage and intracranial pressure following successful mechanical thrombectomy in the acute phase. However, its effect on cognitive impairment remains unclear. This study investigated whether TH can improve cognitive impairment in a mouse model of transient middle cerebral artery occlusion followed by reperfusion (tMCAO/R). Materials and Methods: Nine-week-old C57BL/6N mice (male) were randomly assigned to three groups: sham, tMCAO/R, and tMCAO/R with TH. Cognitive function was assessed 1 month after model induction using the Y-maze test, and regional cerebral glucose metabolism was measured through positron emission tomography with fluorine-18 fluorodeoxyglucose. Results: tMCAO/R induced cognitive impairment, which showed improvement with TH. The TH group exhibited a significant recovery in cerebral glucose metabolism in the thalamus compared to the tMCAO/R group. Conclusions: These findings indicate that TH may hold promise as a therapeutic strategy for alleviating ischemia/reperfusion-induced cognitive impairment.

Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality worldwide. Metabolic disorders such as obesity, diabetes mellitus, dyslipidemia, and metabolic syndrome are associated with CRC risk. Metabolic abnormalities may contribute to colorectal tumorigenesis and reshape the tumor immune microenvironment, which in turn influence immune dysfunction and therapeutic resistance. Exhausted CD8⁺ T cells exhibit impaired effector function, sustained inhibitory receptor expression, and transcriptional and epigenetic reprogramming. Metabolic stressors within the CRC microenvironment may modulate T-cell function and exhaustion-associated states. Additionally, other immune populations (natural killer cells, macrophages, myeloid-derived suppressor cells, dendritic cells, and regulatory T cells) may develop distinct dysfunctional or immunosuppressive states. Recent single-cell and spatial studies have indicated the heterogeneity of these immunometabolic interactions in CRC. This review examines the interactions of the systemic and tumor-associated metabolic alterations with T-cell exhaustion and other forms of immune dysfunction in CRC. We discuss the influence of glucose, lipid, amino acid, and mitochondrial metabolism, hypoxia, microbiota-derived metabolites, and chronic inflammation in shaping tumor–immune interactions. Finally, we reviewed therapeutic strategies targeting immunometabolic pathways and their potential integration with immune checkpoint blockade. Overall, understanding these interactions may help identify immunometabolic vulnerabilities for informing precise therapeutic strategies for CRC.

Therapeutic hypothermia (TH) has emerged as a promising approach with neuroprotective effects that can mitigate secondary brain damage and intracranial pressure in the acute phase after successful mechanical thrombectomy. However, the effect of TH on cognitive impairment has yet fully elucidated. In the present study, we demonstrated whether TH can improve cognitive impairment in a transient middle cerebral artery occlusion (tMCAO) mouse model Nine-week-old C57BL/6N mice (male) were randomized to three groups: sham, tMCAO, and tMCAO with TH. One month after model induction, cognitive function test and regional cerebral glucose metabolism were evaluated using the Y-maze test and positron emission tomography with fluorine-18 fluorodeoxyglucose, respectively. tMCAO led to cognitive impairment, which was improved by TH. The cerebral glucose metabolism of the thalamus was significantly recovered in the TH group compared to that in the tMCAO group. These results suggest that TH might have potential as a therapeutic strategy for improving the ischemia/reperfusion-induced cognitive impairment.

Alzheimer’s disease (AD) is a neurodegenerative disorder defined not only by amyloid-β plaques and tau pathology but also by several interacting processes that drive disease progression. These include neuroinflammation, neuronal cell death, synaptic dysfunction, blood–brain barrier (BBB) breakdown, and myelin and axonal damage. Together, they lead to neuronal loss and cognitive decline. In this review, we present a cell-centered framework linking these processes with key molecular markers. Neuroinflammation is driven by activated microglia and astrocytes and is associated with markers such as Iba1, CD68, GFAP, and C3, along with cytokines including IL-1β and TNF-α. Neuronal cell death occurs through apoptosis, ferroptosis, pyroptosis, and necroptosis, with markers such as caspase-3, GPX4, GSDMD, and MLKL. Synaptic dysfunction is reflected by reduced synaptic proteins, including synaptophysin and PSD-95. BBB breakdown increases permeability and reduces clearance of toxic molecules. Myelin and axonal damage, associated with MBP and NfL, disrupt neural connectivity. These processes are dynamically interconnected and may contribute differently across disease stages. This integrated cell-centered and systems-level framework provides insight into AD progression while highlighting potential biomarkers and therapeutic targets for diagnosis, disease monitoring, and therapeutic intervention.