Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.05.02.722389

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

Fritz, R.·Endres, T.·Schoenwolf, L.·Kartalou, G.-I.·Gottmann, K.·Lessmann, V.
View original source ↗Export metadata ↓

Abstract

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.

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Fritz, R., Endres, T., Schoenwolf, L., Kartalou, G.-I., Gottmann, K., Lessmann, V.. 2026-05-06. The S1PR modulator Ozanimod reverses spine deficits, Amyloid-β plaques deposition and neuroinflammation in aged APP/PS1 mice. https://doi.org/10.64898/2026.05.02.722389

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Connexin 40 deficiency alters the temporal profile of postictal oxygen dynamics following focal seizures.

Epilepsy is increasingly recognized as a disorder involving both neuronal and vascular dysfunction. While connexin signaling has been implicated in epileptogenesis, the contribution of vascular connexins to seizure associated cerebrovascular pathology remains poorly understood. Connexin40 (Cx40) is an endothelial gap junction protein that plays a crucial role in vascular communication and blood-flow regulation. Seizures induce dynamic changes in cerebral perfusion and oxygenation, including prolonged postictal hypoperfusion/hypoxia. To determine whether Cx40 influences postictal hypoxia following focal seizures, we examined seizure characteristics and postictal oxygen dynamics in Cx40 knockout (Cx40-/-) mice using an established focal hippocampal seizure model. Electrically kindled seizures were elicited in wild-type and Cx40-/- mice, and local hippocampal tissue oxygenation was continuously monitored before and after seizure induction. Seizure duration did not differ between genotypes, indicating comparable seizure severity. Interestingly, Cx40 deletion altered the temporal pattern of postictal oxygen recovery, producing greater early hypoxia and a delayed secondary rebound in pO2 despite similar peak oxygen levels and overall hypoxic burden. These findings demonstrate that loss of Cx40 selectively alters the temporal profile of postictal oxygen dynamics without affecting seizure duration. Taken together, the results suggest that endothelial gap junctional communication contributes to postictal vascular recovery and identify Cx40 as a potential modulator of seizure associated neurovascular dysfunction.

neuroscience↗
bioRxiv2026

Attention Across Scales: From Individual Variation to Social Hierarchies and Brain Networks in Semi-Free-Ranging Macaques

Attention is a fundamental brain function supporting perception, decision-making, and social behavior, and its dysfunction profoundly impairs daily life. It is both dynamic and stable, varying across observations and individuals, changing across the lifespan, and being shaped by social and environmental experience. Yet capturing this complexity remains a central challenge in neuroscience. Here, we integrated longitudinal behavioral assessments of semi-free-ranging macaques living in naturalistic social groups with resting-state fMRI. We quantified performance across days, ages, and social hierarchies and related it to intrinsic brain organization. Distinct attentional phenotypes emerged, including individuals with reduced attentional control. Performance followed an inverted-U lifespan trajectory, improving from childhood to adulthood before declining. Social status modulated attentional performance. Critically, nonlinear lifespan trajectories and associations with individual attentional differences were most clearly expressed in frontoparietal connectivity. Together, these findings reveal how sustained attention is organized across scales, providing a biological framework for its individual diversity, social modulation, and neural basis.

neuroscience↗
bioRxiv2026

Decoding natural scenes from patterned optogenetic responses in mouse visual cortex

A central challenge in developing visual cortical prostheses is to determine how visual stimuli should be transformed into effective patterns of cortical stimulation. Although advances in stimulation technologies, including optogenetics, provide increasingly precise control over cortical activity, it remains unclear whether artificially evoked activity can reproduce the information content of naturally evoked visual representations. Here we establish a quantitative framework for evaluating visual encoding strategies by decoding cortical responses evoked by natural vision and patterned optogenetic stimulation. We developed a novel dual-modal paradigm in awake mice to bridge the gap between endogenous photostimulation and artificial network driving. By co-expressing the high-performance calcium indicator GCaMP6s and the red-shifted, ultra-sensitive opsin rsChRmine-oScarlet in the primary visual cortex (V1), we successfully translated dynamic natural movie frames into patterned, spatiotemporal optogenetic stimulation. Quantitative comparisons of macro-scale dynamics demonstrated that this patterned optogenetic injection evokes cortical states highly comparable and representationally aligned with those driven by actual visual photostimulation. To systematically evaluate the fidelity of these responses, we developed STAR, a deep learning model featuring spatial and temporal attention mechanisms, and successfully reconstructed the frames of natural movies from V1 signals under both experimental modalities. Collectively, our results demonstrate that complex sensory information can be both naturally encoded and synthetically injected into V1 circuits with high decoding fidelity. This work provides an empirical and computational proof-of-concept for intelligent, closed-loop biomimetic encoders, establishing a robust framework for next-generation cortical visual neuroprostheses and bidirectional brain-machine interfaces.

neuroscience↗