Daerr, A. | Search bioRxiv

bioRxiv2024

Enhancing Retromer Complex Stability Ameliorates Synaptic Dysfunction in a Mouse Model ofAlzheimer's Disease

Synaptic dysfunction is an early hallmark of Alzheimers disease, characterized by the disruption of synaptic transmission and plasticity. Central to these processes is endosomal trafficking, mediated by the retromer complex, which orchestrates the movement of vesicle contents for recycling to the plasma membrane, return to the Golgi, or degradation. Variants of VPS35, the cargo recognition component of the retromer complex, have been linked to neurodegenerative diseases, including Parkinsons disease (PARK17, D620N mutation) and Alzheimers disease (L625P mutation). While substantial research has focused on Parkinsons, the role of VPS35 in Alzheimers has been less explored. This study investigates the acute neuroprotective effects of retromer-stabilizing compounds in the 5xFAD mouse model of Alzheimers. Our results reveal that stabilization of the retromer complex not only mitigates pathogenic A{beta} production mechanisms but also compensates for early synaptic dysfunction and microglial activation. Specifically, we observed significant modulation of genes involved in long-term potentiation and a reduction in abnormal retromer-associated cargos. These findings highlight the potential of retromer stabilisation as atherapeutic strategy to address fundamental pathological pathological processes in Alzheimers disease.

neuroscience↗

bioRxiv2019

Cooperative pattern formation in multi-species bacterial colonies

Self-organization is a hallmark of all living systems [1]. In particular, coordinated cellular behavior, commonly orchestrated at the population level through reciprocal interactions among different cell species [2-4], regulates the spatial arrangement of specialized cell types to generate tissue patterning and form complex body layouts [5, 6]. The overwhelming complexity of living systems, however, makes deciphering the underlying mechanisms difficult and limits our knowledge of basic pattern-forming mechanism in vivo [7, 8]. A successful strategy is then to work with synthetic, engineered systems, in which cellular interactions can be more easily tailored and studied [9-13]. Here, we demonstrate a simple mechanism through which different populations of cells can self-organize in periodic patterns. Programmed population interactions are shown to lead to coordinated out-ofphase spatial oscillations of two engineered populations of Escherichia coli. Using a combination of experimental and theoretical approaches, we show how such patterns arise autonomously from reciprocal density-dependent activation of cellular motility between the two species, without the need of any preexisting positional or orientational cues. Moreover, by re-designing the interaction, the original out-of-phase spatial oscillation rhythm of the two populations can be accordingly turned into in-phase oscillations. The robustness and versatility of the underlying pattern-formation process suggest that it could both be generically encountered in nature, for instance in the complex bacterial ecosystems found in biofilms [14-16], and used to promote the mixing or demixing of active particles in a controlled way.

biophysics↗