We established experimental models of manganese (Mn) and iron (Fe) exposure in vitro and in vivo, and addressed the effects of manganese and iron combined exposure on the synaptic function of pheochromocytoma derived cell line 12 (PC12) cells and rat cortex, respectively. We investigated the protective effect of sodium para-aminosalicylate (PAS-Na) on manganese and iron combined neurotoxicity, providing a scientific basis for the prevention and treatment of ferromanganese combined neurotoxicity. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to detect the expression levels of protein and mRNA related to synaptic damage. Y-maze novelty test and balance beam test were used to evaluate the motor and cognitive function of rats. Haematoxylin and eosin (H&E) and Nissl staining were performed to observe the cortical damage of rats. The results showed that the combined exposure of Mn and Fe in rats led to a synergistic effect, attenuating growth and development, and altering learning and memory as well as motor function. The combination of Mn and Fe also caused damage to the synaptic structure of PC12 cells, which is manifested as swelling of dendrites and axon terminals, and even lead to cell death. PAS-Na displayed some antagonistic effects against the Mn- and Fe-induced synaptic structural damage, growth, learning and memory impairment.

BACKGROUND: SuanZaoRen Decoction (SZRD), a famous herbal prescription, and has been widely proven to have positive therapeutic effects on insomnia, depression and Alzheimer\'s disease (AD). However, the anti-AD molecular mechanism of SZRD remains to be further investigated.
OBJECTIVE: To elucidate the molecular mechanism of SZRD\'s improvement in AD\'s neuronal loss, synaptic damage and ferroptosis by regulating DJ-1/Nrf2 signaling pathway.
METHODS: LC-MS/MS was used to detect the active ingredients from SZRD. APP/PS1 mice was treated with SZRD and a ferroptosis inhibitor (Liproxstatin-1), respectively. Upon the completion of behavioral tests, Nissl staining, FJB staining, Golgi staining, immunofluorescence, immunohistochemistry, and transmission electron microscopy were preformed to evaluate the effects of SZRD on neuronal loss, synaptic damage, Aβ deposition. Iron staining, transmission electron microscopy, and iron assay kit was performed to estimate the effects of SZRD on ferroptosis. SOD kit, MDA kit, GSH kit, and GSH/GSSG kit were utilized to measure the oxidative stress levels in the hippocampus. The protein expression of TfR1, FTH1, FTL, FPN1, DJ-1, Nrf2, GPX4, SLC7A11, and ACSL4 were detected by Western blot.
RESULTS: A total of 16 active ingredients were identified from SZRD extract. SZRD SZRD significantly alleviated learning and memory impairment in APP/PS1 mice. SZRD improved the hippocampal neuronal loss and degenerated neurons in APP/PS1 mice via inhibiting the Aβ deposit. SZRD mitigated the hippocampal synaptic damage in APP/PS1 mice. SZRD inhibited iron accumulation, and alleviated the oxidative stress level in the hippocampus of APP/PS1 mice. Meanwhile, SZRD could up-regulate the protein expression level of FPN1, DJ-1, Nrf2, GPX4 and SLC7A11 in the hippocampus, and inhibit TfR1, FTH1, FTL, and ACSL4 protein expression.
CONCLUSIONS: SZRD alleviated neuronal loss, synaptic damage and ferroptosis in AD via activating DJ-1/Nrf2 signaling pathway.

Aging-related reduction in androgen levels may be a possible risk factor for neurodegenerative diseases and contribute to cognitive impairment. Androgens may affect synaptic function and cognition in an androgen receptor (AR)-independent manner; however, the mechanisms connecting theses effects are unknown. Therefore, we used testicular feminization mutation (Tfm) male mice, a model with AR mutation, to test the effects of testosterone on synaptic function and cognition. Our results showed that testosterone ameliorated spatial memory deficit and neuronal damage, and increased dendritic spines density and postsynaptic density protein 95 (PSD95) and glutamate receptor 1 (GluA1) expression in the hippocampus of Tfm male mice. And these effects of testosterone were not inhibited by anastrozole, which suppressed conversion of testosterone to estradiol. Mechanistically, testosterone activated the extracellular signal-related kinase 1/2 (Erk1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) in the hippocampus of Tfm male mice. Meanwhile, Erk1/2 inhibitor SCH772984 blocked the upregulation of phospho-CREB, PSD95, and GluA1 induced by testosterone in HT22 cells pretreated with flutamide, an androgen antagonist. Collectively, our data indicate that testosterone may ameliorate hippocampal synaptic damage and spatial memory deficit by activating the Erk1/2-CREB signaling pathway in an AR-independent manner.

Effective preventive measures against postoperative cognitive dysfunction in older adults are urgently needed. In this study, we investigated the effect of electroacupuncture (EA) on anesthesia and surgery-induced cognitive decline in aged rats by RNA-seq analysis, behavioral testing, Golgi-Cox staining, dendritic spine analysis, immunofluorescence assay and western blot analysis. EA ameliorated anesthesia and surgery induced-cognitive decline. RNA-seq analysis identified numerous differentially-expressed genes, including 353 upregulated genes and 563 downregulated genes, after pretreatment with EA in aged rats with postoperative cognitive dysfunction. To examine the role of CREB in EA, we injected adeno-associated virus (AAV) into the CA1 region of the hippocampus bilaterally into the aged rats to downregulate the transcription factor. EA improved synaptic plasticity, structurally and functionally, by activating the MAPK/ERK/CREB signaling pathway in aged rats. Together, our findings suggest that EA protects against anesthesia and surgery-induced cognitive decline in aged rats by activating the MAPK/ERK/CREB signaling pathway and enhancing hippocampal synaptic plasticity.

In addition to amyloid and tau pathology in the central nervous system (CNS), inflammatory processes and synaptic dysfunction are highly important mechanisms involved in the development and progression of dementia diseases. In the present study, we conducted a comparative analysis of selected pro-inflammatory proteins in the CNS with proteins reflecting synaptic damage and core biomarkers in mild cognitive impairment (MCI) and early Alzheimer\'s disease (AD). To our knowledge, no studies have yet compared CXCL12 and CX3CL1 with markers of synaptic disturbance in cerebrospinal fluid (CSF) in the early stages of dementia. The quantitative assessment of selected proteins in the CSF of patients with MCI, AD, and non-demented controls (CTRL) was performed using immunoassays (single- and multiplex techniques). In this study, increased CSF concentration of CX3CL1 in MCI and AD patients correlated positively with neurogranin (r = 0.74; p < 0.001, and r = 0.40; p = 0.020, respectively), ptau181 (r = 0.49; p = 0.040), and YKL-40 (r = 0.47; p = 0.050) in MCI subjects. In addition, elevated CSF levels of CXCL12 in the AD group were significantly associated with mini-mental state examination score (r = -0.32; p = 0.040). We found significant evidence to support an association between CX3CL1 and neurogranin, already in the early stages of cognitive decline. Furthermore, our findings indicate that CXCL12 might be a useful marker for tract severity of cognitive impairment.

Neuroinflammation and synaptic damage are important etiologies associated with the progression of Alzheimer\'s disease (AD). Linderae Radix (LR) has antioxidant and anti-inflammatory properties. This study investigated whether LR attenuates microglia activation-mediated neuroinflammation and synaptic degeneration and improves AD pathological phenotypes induced by amyloid beta oligomers (AβO) or lipopolysaccharide (LPS) toxicity. For in vitro studies, we treated LR to AβO-stimulated HT22 cells or LR LPS-stimulated BV2 cells. For in vivo studies, we administered LR to mice and AβO was injected by stereotaxic to induce cognitive impairment, neuroinflammation, and synaptic loss. We found that LR increased the cell viability reduced by AβO. Moreover, LR inhibited pro-inflammatory mediators such as nitric oxide (NO), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2), and downregulated p38 mitogen-activated protein kinase (MAPK) signaling in BV2 cells. Behavioral assessments demonstrated that LR administration significantly improved cognitive decline induced by AβO-injection. Furthermore, we found that microglia activation increased, and the expression of synaptic proteins decreased in the hippocampus of the AβO-injected group, which was alleviated in the LR-treated group. These findings suggest that LR may be a potential candidate for protection against neuroinflammation and synaptic loss, and may prevent or delay AD progression.

Polygala tenuifolia was documented to calm the mind and promote wisdom. However, its underlying mechanisms are still unclear. This study aimed to investigate the mechanisms underlying the effects of tenuifolin (Ten) on Alzheimer\'s disease (AD)-like phenotypes. We first applied bioinformatics methods to screen the mechanisms of P. tenuifolia in the treatment of AD. Thereafter, the d-galactose combined with Aβ1-42 (GCA) was applied to model AD-like behaviors and investigate the action mechanisms of Ten, one active component of P. tenuifolia. The data showed that P. tenuifolia actioned through multi-targets and multi-pathways, including regulation of synaptic plasticity, apoptosis, and calcium signaling, and so forth. Furthermore, in vitro experiments demonstrated that Ten prevented intracellular calcium overload, abnormal calpain system, and down-regulation of BDNF/TrkB signaling induced by GCA. Moreover, Ten suppressed oxidative stress and ferroptosis in HT-22 cells induced by GCA. Calpeptin and ferroptosis inhibitor prevented the decrease of cell viability induced by GCA. Interestingly, calpeptin did not interrupt GCA-induced ferroptosis in HT-22 cells but blocked the apoptosis. Animal experiments further demonstrated that Ten prevented GCA-induced memory impairment in mice and increased synaptic protein expression while reducing m-calpain expression. Ten prevents AD-like phenotypes through multiple signaling by inhibiting oxidative stress and ferroptosis, maintaining the stability of calpain system, and suppressing neuronal apoptosis.

Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by the overstimulation of ionotropic glutamate receptors. Although dysregulation of proteolytic signaling networks is critical for excitotoxicity, the identity of affected proteins and mechanisms by which they induce neuronal cell death remain unclear. To address this, we used quantitative N-terminomics to identify proteins modified by proteolysis in neurons undergoing excitotoxic cell death. We found that most proteolytically processed proteins in excitotoxic neurons are likely substrates of calpains, including key synaptic regulatory proteins such as CRMP2, doublecortin-like kinase I, Src tyrosine kinase and calmodulin-dependent protein kinase IIβ (CaMKIIβ). Critically, calpain-catalyzed proteolytic processing of these proteins generates stable truncated fragments with altered activities that potentially contribute to neuronal death by perturbing synaptic organization and function. Blocking calpain-mediated proteolysis of one of these proteins, Src, protected against neuronal loss in a rat model of neurotoxicity. Extrapolation of our N-terminomic results led to the discovery that CaMKIIα, an isoform of CaMKIIβ, undergoes differential processing in mouse brains under physiological conditions and during ischemic stroke. In summary, by identifying the neuronal proteins undergoing proteolysis during excitotoxicity, our findings offer new insights into excitotoxic neuronal death mechanisms and reveal potential neuroprotective targets for neurological disorders.

Bisphenol A (BPA) has been widely restricted, leading to a significant increase in the production of bisphenol AF (BPAF), one of the most common bisphenol analogs use as a substitute for BPA. However, there is limit evidence on the neurotoxicity of BPAF, especially the potential effects of maternal exposed to BPAF on offspring. A maternal BPAF exposure model was used to evaluate its effects on long-term neurobehaviors in offspring. We found that maternal BPAF exposure resulted in immune disorders, characterized by abnormal CD4+T cell subsets, and their offspring exhibited anxiety- and depression-like behaviors, as well as impairments in learning-memory, sociability and social novelty. Further, brain bulk RNA-sequencing (RNA-seq) and hippocampus single-nucleus RNA-sequencing (snRNA-seq) of offspring showed that differentially expressed genes (DEGs) were enriched in pathways related to synaptic and neurodevelopment. Synaptic ultra-structure of offspring was damaged after maternal BPAF exposure. In conclusion, maternal BPAF exposure induced behavior abnormality in adult offspring, together with synaptic and neurodevelopment defects, which might be related to maternal immune dysfunction. Our results provide a comprehensive insight into the neurotoxicity mechanism of maternal BPAF exposure during gestation. Given the increasing and ubiquitous exposure to BPAF, especially during sensitive periods of growth and development, the safety of BPAF requires urgent attention.

UNASSIGNED: Blast induced Traumatic Brain Injury (bTBI) has become a signature casualty of military operations. Recently, military medics observed neurocognitive deficits in servicemen exposed to repeated low level blast (LLB) waves during military heavy weapons training. In spite of significant clinical and preclinical TBI research, current understanding of injury mechanisms and short- and long-term outcomes is limited. Mathematical models of bTBI biomechanics and mechanobiology of sensitive neuro-structures such as synapses may help in better understanding of injury mechanisms and in the development of improved diagnostics and neuroprotective strategies.
UNASSIGNED: In this work, we formulated a model of a single synaptic structure integrating the dynamics of the synaptic cell adhesion molecules (CAMs) with the deformation mechanics of the synaptic cleft. The model can resolve time scales ranging from milliseconds during the hyperacute phase of mechanical loading to minutes-hours acute/chronic phase of injury progression/repair. The model was used to simulate the synaptic injury responses caused by repeated blast loads.
UNASSIGNED: Our simulations demonstrated the importance of the number of exposures compared to the duration of recovery period between repeated loads on the synaptic injury responses. The paper recognizes current limitations of the model and identifies potential improvements.