RESUMEN
A pathological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-ß (Aß) protein in the brain. Physical exercise has been shown to reduce Aß burden in various AD mouse models, but the underlying mechanisms have not been elucidated. Irisin, an exercise-induced hormone, is the secreted form of fibronectin type-III-domain-containing 5 (FNDC5). Here, using a three-dimensional (3D) cell culture model of AD, we show that irisin significantly reduces Aß pathology by increasing astrocytic release of the Aß-degrading enzyme neprilysin (NEP). This is mediated by downregulation of ERK-STAT3 signaling. Finally, we show that integrin αV/ß5 acts as the irisin receptor on astrocytes required for irisin-induced release of astrocytic NEP, leading to clearance of Aß. Our findings reveal for the first time a cellular and molecular mechanism by which exercise-induced irisin attenuates Aß pathology, suggesting a new target pathway for therapies aimed at the prevention and treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Neprilisina , Ratones , Animales , Neprilisina/genética , Neprilisina/metabolismo , Fibronectinas/metabolismo , Regulación hacia Abajo , Astrocitos/metabolismo , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismoRESUMEN
Brain infiltration of peripheral immune cells and their interactions with brain-resident cells may contribute to Alzheimer's disease (AD) pathology. To examine these interactions, in the present study we developed a three-dimensional human neuroimmune axis model comprising stem cell-derived neurons, astrocytes and microglia, together with peripheral immune cells. We observed an increase in the number of T cells (but not B cells) and monocytes selectively infiltrating into AD relative to control cultures. Infiltration of CD8+ T cells into AD cultures led to increased microglial activation, neuroinflammation and neurodegeneration. Using single-cell RNA-sequencing, we identified that infiltration of T cells into AD cultures led to induction of interferon-γ and neuroinflammatory pathways in glial cells. We found key roles for the C-X-C motif chemokine ligand 10 (CXCL10) and its receptor, CXCR3, in regulating T cell infiltration and neuronal damage in AD cultures. This human neuroimmune axis model is a useful tool to study the effects of peripheral immune cells in brain disease.
Asunto(s)
Enfermedad de Alzheimer , Linfocitos T CD8-positivos , Humanos , Neuroinmunomodulación , Neuroglía , NeuronasRESUMEN
Slides showcasing research of one or two neuroscientists from diverse backgrounds were added to weekly, learning assistant-led sections in a large (~80 person) primarily lecture course required for neuroscience majors. Students appreciated the slides, and survey data suggests that the slides increased the sense of belonging for both underrepresented and not underrepresented students.