Małgorzata Alicja Śliwińska

The prevailing view frames microglia and macrophages as guardians against amyloid beta (Aβ) accumulation in Alzheimer’s disease (AD). Here, we overturn this paradigm by demonstrating that human phagocytic cells, including differentiated THP-1 macrophages and hESC-derived microglia, are not merely passive responders but active producers of extracellular, seeding-competent Aβ42 fibrils, the amyloid species most strongly linked to parenchymal plaque formation and neurodegeneration. These cell-generated aggregates differ structurally and functionally from synthetic fibrils, displaying enhanced seeding and tau cross-seeding activity in biosensor models. Notably, Aβ42 fibril formation in this system requires active cellular processes and is exacerbated by loss of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a major AD risk gene. Transcriptomic profiling reveals an early inflammatory response resembling microglial states observed in human AD models. Together, these findings support emerging evidence from in vivo studies that macrophages and microglia can influence amyloid seeding and introduce a human-relevant in vitro platform to explore how Aβ aggregation intersects with innate immune function and genetic risk. Our results reinforce the concept that microglia may play a dual role in AD, acting both as responders and inadvertent facilitators of amyloid assembly, with implications for early therapeutic intervention.

Ferroptosis, a regulated form of cell death driven by lipid peroxidation, holds promise for targeting treatment-resistant cancer cells. Using a panel of melanoma cell lines, we uncover variability in the timing of ferroptosis onset upon exposure to iron and polyunsaturated fatty acids (PUFAs). This heterogeneity is linked to differences in PUFA sequestration into lipid droplets (LDs) and their subcellular distribution, particularly near lipid-metabolizing organelles such as mitochondria. In late-onset models, ferroptosis is delayed by peripheral LD retention and triggered by nutrient deprivation and AMP-activated protein kinase (AMPK) activation, which promotes LD trafficking toward mitochondria. Early responders bypass this mechanism. Our findings identify nutrient status and LD dynamics as key modulators of PUFA- and iron-induced ferroptosis, offering insights for therapeutic exploitation in cancer.

The ability to extinguish contextual fear in a changing environment is crucial for animal survival. Recent data support the role of the thalamic nucleus reuniens (RE) and its projections to the dorsal hippocampal CA1 area (RE→dCA1) in this process. However, it remains poorly understood how RE impacts dCA1 neurons during contextual fear extinction (CFE). Here, we reveal that the RE→dCA1 pathway contributes to the extinction of contextual fear by affecting CFE-induced molecular remodeling of excitatory synapses. Anatomical tracing and chemogenetic manipulation in mice demonstrate that RE neurons form synapses and regulate synaptic transmission in the stratum oriens (SO) and lacunosum-moleculare (SLM) of the dCA1 area, but not in the stratum radiatum (SR). We also observe CFE-specific structural changes of excitatory synapses and expression of the synaptic scaffold protein, PSD-95, in both strata innervated by RE, but not in SR. Interestingly, only the changes in SLM are specific for the dendrites innervated by RE. To further support the role of the RE→dCA1 projection in CFE, we demonstrate that brief chemogenetic inhibition of the RE→dCA1 pathway during a CFE session persistently impairs the formation of CFE memory and CFE-induced changes of PSD-95 levels in SLM. Thus, our data indicate that RE participates in CFE by regulating CFE-induced molecular remodeling of dCA1 synapses.

The neuropeptide corticotropin-releasing factor (CRF) exerts a pivotal role in modulating neuronal activity in the mammalian brain. The effects of CRF exhibit notable variations, depending on factors such as duration of exposure, concentration, and anatomical location. In the CA1 region of the hippocampus, the impact of CRF is dichotomous: chronic exposure to CRF impairs synapse formation and dendritic integrity, whereas brief exposure enhances synapse formation and plasticity. In the current study, we demonstrate long-term effects of acute CRF on the density and stability of mature mushroom spines ex vivo. We establish that both CRF receptors are present in this hippocampal region, and we pinpoint their precise subcellular localization within synapses by electron microscopy. Furthermore, both in vivo and ex vivo data collectively demonstrate that a transient surge of CRF in the CA1 activates the cyclin-dependent kinase 5 (Cdk5)-pathway. This activation leads to a notable augmentation in CRF-dependent spine formation. Overall, these data suggest that upon acute release of CRF in the CA1-SR synapse, both CRF-Rs can be activated and promote synaptic plasticity via activating different downstream signaling pathways, such as the Cdk5-pathway.

We studied the spatial conformation and activity of mitochondria in the developing syncytial male germline cysts during spermatogenesis of the medicinal leeches using light, fluorescent, transmission electron microscopy, and serial block-face scanning electron microscopy. In cysts with spermatogonia and spermatocytes, mitochondria form networks and are in a dynamic hyperfusion state, while in cysts with spermatids, a single huge mitochondrion is observed. As spermiogenesis progresses, this huge mitochondrion is finally located in the future midpiece. The highest activity, in terms of membrane potential, of the mitochondria in H. medicinalis germline cysts was observed in cysts with spermatocytes; the lowest was in cysts with late elongated spermatids.

Calcium/calmodulin‐dependent kinase II (CaMKII) is a key enzyme at the glutamatergic synapses. CAMK2A gene variants have been linked with alcohol use disorder (AUD) by an unknown mechanism. Here, we looked for the link between αCaMKII autophosphorylation and the AUD aetiology. Autophosphorylation‐deficient heterozygous αCaMKII mutant mice (T286A^+/−) were trained in the IntelliCages to test the role of αCaMKII activity in AUD‐related behaviours. The glutamatergic synapses morphology in CeA was studied in the animals drinking alcohol using 3D electron microscopy. We found that T286A^+/− mutants consumed less alcohol and were more sensitive to sedating effects of alcohol, as compared to wild‐type littermates (WT). After voluntary alcohol drinking, T286A^+/− mice had less excitatory synapses in the CeA, as compared to alcohol‐naive animals. This change correlated with alcohol consumption was not reversed after alcohol withdrawal and not observed in WT mice. Our study suggests that αCaMKII autophosphorylation affects alcohol consumption by controlling sedative effects of alcohol and preventing synaptic loss in the individuals drinking alcohol. This finding advances our understanding of the molecular processes that regulate alcohol dependence.

The order of Cyanidiales comprise seven acido-thermophilic red microalgal species thriving in hot springs of volcanic origin characterized by extremely low pH, moderately high temperatures and the presence of elevated concentrations of sulphites and heavy metals that are prohibitive for most other organisms. Little is known about the molecular mechanisms of Cyanidiales long-term adaptation to such hostile environments, in particular to heavy metals, yet elucidation of these processes is important for understanding the evolution of the metabolic pathways underlying heavy metal detoxification for developing rational strategies for heavy metal bioremediation. Here, we investigated the long-term adaptive responses of Cyanidioschyzon merolae cells, a member of Cyanidiales, to extremely high nickel concentrations. Through complementary approaches based on physiological, microscopic and elemental analyses we dissect several molecular mechanisms underlying the long-term adaptation of this model extremophilic microalga to high Ni exposure. These include: (i) extrusion of Ni from the cells and lack of significant Ni accumulation inside the cells; (ii) maintenance of efficient photoprotective responses including non-photochemical quenching and state transitions; (iii) dynamic remodeling of the chloroplast ultrastructure such as formation of metabolically active prolamellar bodies and plastoglobuli together with loosening of the thylakoid membranes; (iv) activation of ROS amelioration metabolic pathways; and (v) preservation of the efficient respiratory chain functionality. All the dynamically regulated processes identified in this study underlie the remarkable adaptability of C. merolae to extremely high Ni levels that exceed by several orders of magnitude the levels of this heavy metal found in the natural environment of this extremophile.

Calcium/calmodulin-dependent kinase II (CaMKII) is a key enzyme at the glutamatergic synapses. CAMK2A gene variants have been linked with alcohol use disorder (AUD) by an unknown mechanism. Here, we looked for the link between αCaMKII autophosphorylation and the AUD etiology. Autophosphorylation-deficient heterozygous αCaMKII mutant mice (T286A^+/-) were trained in the IntelliCages to test the role of αCaMKII activity in AUD-related behaviors. The glutamatergic synapses morphology in CeA was studied in the animals drinking alcohol using 3D electron microscopy. We found that T286A^+/- mutants consumed less alcohol and were more sensitive to sedating effects of alcohol, as compared to wild-type littermates (WT). After voluntary alcohol drinking T286A^+/- mice had less excitatory synapses in the CeA, as compared to alcohol-naive animals. This change correlated with alcohol consumption, was not reversed after alcohol withdrawal and not observed in WT mice. Our study suggests that αCaMKII autophosphorylation affects alcohol consumption by controlling sedative effects of alcohol and preventing synaptic loss in the individuals drinking alcohol. This finding advances our understanding of the molecular processes that regulate alcohol misuse.

The updating of contextual memories is essential for survival in a changing environment. Accumulating data indicate that the dorsal CA1 area (dCA1) contributes to this process. However, the cellular and molecular mechanisms of contextual fear memory updating remain poorly understood. Postsynaptic density protein 95 (PSD-95) regulates the structure and function of glutamatergic synapses. Here, using dCA1-targeted genetic manipulations in vivo , combined with ex vivo 3D electron microscopy and electrophysiology, we identify a novel, synaptic mechanism that is induced during attenuation of contextual fear memories and involves phosphorylation of PSD-95 at Serine 73 in dCA1. Our data provide the proof that PSD-95-dependent synaptic plasticity in dCA1 is required for updating of contextual fear memory.