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Hee-Seok Kweon

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Open access Sep 2026

Ursolic acid attenuates LPS-induced cognitive dysfunction through the modulation of oxidative stress, neuroinflammation, and hippocampal synaptic plasticity.

BACKGROUND Neuroinflammation and oxidative stress play vital roles in the pathogenesis of neurodegenerative diseases characterized by cognitive decline. Ursolic acid (UA), a natural pentacyclic triterpenoid compound with reported anti-inflammatory and antioxidant properties, has been suggested as a potential neuroprotective agent. PURPOSE This study was conducted to clarify whether UA attenuates lipopolysaccharide (LPS)-induced neurotoxicity through redox regulation, mitochondrial protection, and modulation of neurotrophic signaling. STUDY DESIGN An in vivo mouse model of LPS-induced neuroinflammation and cognitive impairment was used to evaluate the neuroprotective effects of UA. METHODS Mice were administered LPS (10 µg/µl) via intracerebroventricular injection to induce neuroinflammation and cognitive impairment and were subsequently treated with UA (50 or 100 mg/kg, intraperitoneally). Behavioral tests were performed to assess learning and memory. Oxidative stress markers in hippocampal tissues were analyzed, together with inflammatory mediators and brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB)-cAMP response element-binding protein (CREB) signaling by western blot. Glial activation was examined by immunofluorescence, and hippocampal ultrastructure was evaluated using transmission electron microscopy and serial section-based three-dimensional electron microscopy. RESULTS UA treatment improved LPS-induced learning and memory deficits, reduced oxidative damage, and restored antioxidant enzyme activities in the hippocampus in a dose-related manner. The higher dose (UA2, 100 mg/kg) generally exerted a stronger restorative effect than the lower dose (UA1, 50 mg/kg). It also suppressed microglial overactivation and nuclear factor kappa B-mediated inflammatory signaling along with reducing the expression of proinflammatory mediators. UA also restored hippocampal BDNF-TrkB-CREB signaling, which is essential for synaptic plasticity and memory formation. Ultrastructural analyses revealed preservation of neuronal and synaptic architecture and normalization of mitochondrial morphology, with reduced mitochondrial fragmentation and mitochondria-on-a-string dynamics. CONCLUSION UA mitigates LPS-induced cognitive deficits by modulating oxidative and inflammatory signaling, reactivating BDNF-TrkB-CREB signaling, and stabilizing mitochondrial homeostasis. These findings emphasize the therapeutic potential of UA as a natural redox-modulating neuroprotective agent for inflammation-associated cognitive dysfunction.

Ga-Young Choi, Seohyeong Lee, A. Je et al. · Phytomedicine · 0 citations

Open access Aug 2026

Neuronal AIMP2–α-synuclein synergy drives endogenous tau and amyloid-β pathologies and neurodegeneration in a mechanistic model of Lewy body dementia

Lewy body dementia (LBD), encompassing Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), is defined by widespread α-synuclein (αSyn) aggregation and frequently exhibits coexistent tau and amyloid-β (Aβ) pathologies. However, whether αSyn pathology is sufficient to drive endogenous tau and Aβ aggregation has remained unclear due to a lack of in vivo models that recapitulate the full spectrum of LBD-associated proteinopathies and neurodegeneration. AIMP2, a parkin substrate that accumulates in Parkinson’s disease, enhances αSyn aggregation and toxicity, but its role in initiating downstream mixed pathologies across vulnerable brain regions has not been demonstrated in vivo. Here, we generated a conditional, neuron-specific Tet-Off double-transgenic mouse model enabling post-developmental coexpression of AIMP2 and A53T αSyn. This synergistic coexpression induced rapid and widespread αSyn aggregation, detergent-insoluble Lewy-like inclusions, mitochondrial degeneration, synaptic impairment, and neuronal loss, accompanied by marked gliosis. Mice developed key clinical features of LBD, including progressive cognitive impairment, bradykinesia, and olfactory deficits. Notably, without tau or APP overexpression, endogenous tau became hyperphosphorylated through dysregulated kinase signaling, and Aβ accumulated predominantly as TBS-soluble Aβ42 monomers/oligomers without fibrillar plaque deposition, demonstrating that AIMP2–αSyn–driven pathology is sufficient to trigger downstream tauopathy and Aβ pathologies. These mixed pathologies were associated with lysosomal and proteasomal dysfunction, evidenced by p62 and polyubiquitinated protein accumulation. Proteomic analysis identified dysregulation of pathways linked to amyloid processing, synaptic trafficking, and protein quality control. Importantly, temporal suppression of AIMP2 and αSyn expression promoted reduction of pre-existing pathologies and partially restored cognitive function. This study establishes a genetically controlled in vivo model of LBD-like mixed proteinopathy recapitulating αSyn aggregation, tau hyperphosphorylation, Aβ accumulation, neurodegeneration, and behavioral decline. These findings support a mechanistic link between AIMP2-enhanced αSyn toxicity and secondary proteinopathies and position this model as a platform for mechanistic and therapeutic studies in complex α-synucleinopathies.

Doeun Kim, Hee-Tae Kim, Ji Hun Kim et al. · Cell Death & Disease · 0 citations