Biology subjects

Gottmann, K.

Publications and source records attributed to Gottmann, K..

3 recordsLinked to original sources

bioRxiv2026

The S1PR modulator Ozanimod reverses spine deficits, Amyloid-β plaques deposition and neuroinflammation in aged APP/PS1 mice

Innovative therapeutic approaches providing clinically effective medication for Alzheimers disease (AD) patients are urgently needed. In recent years, monoclonal antibodies against Amyloid-{beta} (A{beta}) oligomers were approved as the first disease modifying AD therapies. However, their effects on cognitive decline of AD patients are still limited - most likely because neuroinflammatory processes downstream of A{beta} plaques remain activated, even when plaques are depleted. Accordingly, anti-inflammatory drugs are currently considered as valuable (co-)treatments to target A{beta} associated neuro-inflammation. The anti-inflammatory sphingosine-1-phosphate receptor (S1PR) modulator fingolimod (FTY720) has been shown to alleviate synaptic and cognitive deficits in numerous mouse models of AD. Whether other S1PR modulators exert similar beneficial effects is largely unknown. Here we used a transgenic APP/PS1 AD mouse model to investigate whether the S1PR modulator Ozanimod (RPC1063) can rescue AD pathology and synaptic dysfunctions even when treatment is initiated at 16-17 months of age, which is 10 months after onset of cognitive deficits. We performed quantitative dendritic spine analysis in hippocampal CA1 pyramidal neurons and immunohistochemical labelling of Iba1-positive activated microglia, GFAP-positive reactive astrocytes, and A{beta} plaques in hippocampus and neocortex. Our results reveal that 6 weeks of Ozanimod treatment via drinking water rescues synaptic spine deficits, counteracts A{beta} pathology and reduces neuro-inflammation in the hippocampus and neocortex of APP/PS1 mice. Therefore, it might hold promise to examine a potential disease-modifying effect of S1PR modulators in clinical trials with AD patients.

neuroscience↗

bioRxiv2021

Transsynaptic N-cadherin adhesion complexes control presynaptic vesicle and bulk endocytosis at physiological temperature

At mammalian glutamatergic synapses, most basic elements of synaptic transmission have been shown to be modulated by specific transsynaptic adhesion complexes. However, although crucial for synapse homeostasis, a physiological regulation of synaptic vesicle endocytosis by adhesion molecules has not been firmly established. The homophilic adhesion protein N-cadherin is localized at the peri-active zone, where the highly temperature dependent endocytosis of vesicles occurs. Here, we demonstrate an important modulatory role of N-cadherin in endocytosis at near physiological temperature by synaptophysin-pHluorin imaging. Different modes of endocytosis including bulk endocytosis were dependent on N-cadherin expression and function. N-cadherin modulation was mediated by actin filaments, because actin polymerization rescued the knockout induced endocytosis defect. Using super-resolution imaging, we found a strong recruitment of N-cadherin to glutamatergic synapses upon massive vesicle release, which might in turn enhance vesicle endocytosis. This provides a novel, adhesion protein mediated mechanism for efficient coupling of exo- and endocytosis.

neuroscience↗

bioRxiv2019

Anti-inflammatory treatment with FTY720 starting after onset of symptoms reverses synaptic and memory deficits in an AD mouse model

Therapeutical approaches providing effective medication for Alzheimers disease (AD) patients after disease onset are urgently needed. Repurposing FDA approved drugs like fingolimod (FTY720) for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms. Here, we addressed whether the FDA approved drug fingolimod rescues AD related synaptic deficits and memory dysfunction in an APP/PS1 AD mouse model when medication starts after onset of symptoms (at 5 months). Male mice received intraperitoneal injections of fingolimod for 1-2 months starting at 5-6 months. This treatment rescued spine density as well as long-term potentiation in hippocampal CA1 pyramidal neurons, and ameliorated dysfunctional hippocampus-dependent memory that was observed in untreated APP/PS1 animals at 6-7 months of age. Immunohistochemical analysis with markers of microgliosis (Iba1) and astrogliosis (GFAP) revealed that our fingolimod treatment regime strongly down regulated neuro-inflammation in the hippocampus and cortex of this AD model. These effects were accompanied by a moderate reduction of A{beta} accumulation in hippocampus and cortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology and related memory performance deficits observed in untreated AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.

neuroscience↗