Project description:Extracellular matrix (ECM) remodeling is strongly linked to Alzheimer’s disease (AD) risk, but its functions are not fully understood. Here, we found that medial prefrontal cortex (mPFC) injection with chondroitinase ABC (ChABC) to remodel ECM reverses short-term memory loss and reduces Aβ deposition in 5xFAD mice. ECM remodeling also reactivates astrocytes, untangles aggrecan’s entanglement with amyloid-beta (Aβ) plaques, and encourages astrocyte recruitment to the surrounding plaques. ECM remodeling promotes astrocyte phagocytosis of Aβ plaque by activating the astrocyte phagocytosis receptor mertk and astrocytic vesicle circulation. Importantly, ECM remodeling enhances the autophagy-lysosome pathway in astrocytes to mediate Aβ clearance and alleviate AD pathology. Our work thus discovers a cellular mechanism to remodel the ECM to active astrocyte autophagic lysosomal pathway alleviation AD pathology. It may represent a potential therapeutic strategy and serve as a hallmark for treating AD.
Project description:Central nervous system (CNS) resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including Multiple Sclerosis (MS). Several studies have demonstrated the involvement of pro- inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from MS patients in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a novel modulator of autoimmune CNS inflammation and potential therapeutic target in MS.
Project description:Central nervous system (CNS) resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including Multiple Sclerosis (MS). Several studies have demonstrated the involvement of pro- inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from MS patients in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a novel modulator of autoimmune CNS inflammation and potential therapeutic target in MS.
Project description:The physical manifestations of memory formation and recall are fundamental questions that remain unresolved. At the cellular level, ensembles of neurons called engrams are activated by learning events and control memory recall. Astrocytes are in close proximity to neurons and engage in a range of activities that support neurotransmission and circuit plasticity. Moreover, astrocytes exhibit experience dependent plasticity; however whether specific ensembles of astrocytes participate in memory recall remains obscure. Here we show that learning events induce c-Fos expression in a subset of hippocampal astrocytes, which subsequently regulates hippocampal circuit function. Intersectional, c-Fos based labeling of these astrocyte ensembles after learning events reveals that they are closely affiliated with engram neurons, while re-activation of these astrocyte ensembles stimulates memory recall. At the molecular level, these astrocyte ensembles exhibit elevated expression of NFIA and its selective deletion from this population suppresses memory recall. Together, our studies identify learning-associated astrocyte ensembles as a new form of plasticity that is sufficient to provoke memory recall, while implicating astrocytes as a reservoir for the storage of memories.