Ramonet, D. | bioRxiv Science

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↗

bioRxiv2021

Microglial phagocytosis dysfunction during stroke is prevented by rapamycin

Microglial phagocytosis is rapidly emerging as a therapeutic target in neurodegenerative and neurological disorders. An efficient removal of cellular debris is necessary to prevent buildup damage of neighbor neurons and the development of an inflammatory response. As the brain professional phagocytes, microglia are equipped with an array of mechanisms that enable them to recognize and degrade several types of cargo, including neurons undergoing apoptotic cell death. While microglia are very competent phagocytes of apoptotic cells under physiological conditions, here we report their dysfunction in mouse and monkey (Macaca fascicularis and Callithrix jacchus) models of stroke by transient occlusion of the medial cerebral artery (tMCAo). The impairment of both engulfment and degradation was related to energy depletion triggered by oxygen and nutrients deprivation (OND), which led to reduced process motility, lysosomal depletion, and the induction of a protective autophagy response in microglia. Basal autophagy, which is in charge of removing and recycling intracellular elements, was critical to maintain microglial physiology, including survival and phagocytosis, as we determined both in vivo and in vitro using knock-out models of autophagy genes and the autophagy inhibitor MRT68921. Notably, the autophagy inducer rapamycin partially prevented the phagocytosis impairment induced by tMCAo in vivo but not by OND in vitro. These results suggest a more complex role of microglia in stroke than previously acknowledged, classically related to the inflammatory response. In contrast, here we demonstrate the impairment of apoptotic cell phagocytosis, a microglial function critical for brain recovery. We propose that phagocytosis is a therapeutic target yet to be explored and provide evidence that it can be modulated in vivo using rapamycin, setting the stage for future therapies for stroke patients.

neuroscience↗