Biology subjects

Leitinger, G.

Publications and source records attributed to Leitinger, G..

3 recordsLinked to original sources

bioRxiv2025

Amyloid beta aggregation promoted by iron leads to neuronal loss in an ex vivo model of Alzheimer's disease

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta (A{beta}) plaques and neurofibrillary tangles. Despite well-established iron accumulation in the AD brain, its role in exacerbating A{beta} toxicity is often overlooked in therapeutic research. We developed a 3D ex vivo organotypic brain slice cultures (OBSC) with A{beta} monomers and ferric citrate to mimic A{beta} deposits and iron overload to investigate the impact of excess iron on A{beta} toxicity in pig and human brains. Light and electron microscopy, biochemical assays, and multiple regression modeling were employed to assess iron-mediated A{beta} toxicity in neurons and glial cells. We show that OBSC offer a close approximation of in vivo morphological and physiological properties and can retain both neurons and glial cells for extended periods, and respond to experimental manipulations. We show that iron promotes A{beta} fibrillization into long fibrils, with this process further influenced by temperature. A{beta} selectively accumulated in neurons, leading to their death, sparing glial cells. In contrast, Iron, though generally toxic to neurons, exhibited unspecific cytotoxicity. Notably, the combined presence of A{beta} and iron synergistically increased neuronal death while reducing glial cell loss. Correlation analysis revealed that this synergic interaction enhances the toxicity of each other in a mutual fashion - A{beta} directs the neuronal toxicity while iron promotes A{beta} fibrillization, leading to targeted neuronal loss. In conclusion, our findings emphasize the critical role of excess iron and A{beta} in driving neuronal death in AD, underlining the importance of targeting iron accumulation along with A{beta} clearance but also addressing in future AD therapies, while also supporting our OBSC model as a valuable platform for studying the same.

neuroscience↗

bioRxiv2024

Recurrent drought increases grassland community seasonal synchrony

1. Climate change increases the frequency and severity of drought events with strong repercussions on grassland ecosystems. While the effects of single drought events on ecosystem structure and functioning are well understood, it is largely unknown whether and how drought frequency modifies ecosystem responses to drought. 2. Here, we assessed how the increase in frequency of severe, annual summer drought impacted grassland communities. We examined these effects in a species-rich sub-alpine mountain meadow with a drought frequency of one, three, and 13 years, as well as ambient conditions. 3. We found that high drought frequency increased seasonal plant community synchrony through a reduction in species richness, a shift of plant functional groups, a loss of early-seasonal plant species, and the constrained establishment of seedlings throughout the growing season. These changes were associated with a decreased fraction of biomass as drought frequency increased. 4. Furthermore, we show that negative drought effects were enhanced with an increasing drought frequency, and that negative drought effects on plant communities outweighed the weak adaptive effects of species. 5. Synthesis. We conclude that single and low-frequency drought studies may not adequately predict longer-term changes in our rapidly shifting climate. With the ongoing increase in drought frequency due to climate change, we predict that grassland plant communities will increase in seasonal synchrony. We suggest that this increase in synchrony will leave ecosystems highly vulnerable to future disturbances, because asynchrony is a critical component of stability. Moreover, given the weak adaptive effects of plant species to long-term recurrent drought, we conclude that plant communities are unlikely to be able to adapt to the rapid increase in recurrent drought events.

ecology↗

bioRxiv2022

Changes in cellular ferritin distribution of human brain tissue during autolysis revealed using analytical electron microscopy

Iron is known to accumulate in neurological disorders, so a careful balance of the iron concentration is essential for healthy brain functioning. An imbalance in iron homeostasis could arise due to the dysfunction of the proteins involved in iron homeostasis. Here, we focus on ferritin - the primary iron storage protein of the brain. Though it is known that glial cells and neurons differ in their concentration of ferritin, the change in the number of iron-filled ferritin cores or their distribution between different cell types during autolysis has not been revealed yet. Here, we show the cellular and region-wide distribution of ferritin in the human brain using state-of-the-art analytical electron microscopy. We validated the concentration of iron-filled ferritin cores to the absolute iron concentration measured by quantitative MRI and inductively coupled plasma mass spectrometry. We show that ferritins lost iron from their cores with progressing autolysis whereas the overall iron concentrations were unaffected. Though the highest concentration of ferritins was found in glial cells, we found that as the total ferritin concentration increased in a patient, ferritin accumulated more in neurons than in glial cells. Collectively our findings point out the unique behaviour of neurons in storing iron during autolysis and explain the differences between the absolute iron concentrations and iron-filled ferritin in a cell-type-dependent fashion in the human brain. Significance statementBalance of the iron load of the brain is crucial to preventing neurodegenerative disorders. Our study establishes a relation between autolysis, iron, and ferritin in the human brain with emphasis on the role of different cells in ferritin storage. We demonstrate that the iron load of ferritins does not correlate with mean iron concentrations during autolysis. Neurons retain more iron-loaded ferritin than glial cells with increasing ferritin count, which may make neurons more susceptible and exacerbate neuronal loss during iron overload. Neurons are also depleted of iron-loaded ferritin cores faster than glial cells during autolysis, demonstrating their unique role in iron storage. This paves the way to understanding the respective roles of neurons and glial cells in preventing or promoting neurodegeneration.

neuroscience↗