The complement system is part of the innate immune response responsible for removing pathogens and cellular debris, in addition to helping to refine CNS neuronal connections via microglia-mediated pruning of inappropriate synapses during brain development. However, less is known about the role of complement during normal aging. Here, we studied the role of the central complement component, C3, in synaptic health and aging. We examined behavior as well as electrophysiological, synaptic, and neuronal changes in the brains ofC3-deficient male mice (C3KO) compared with age-, strain-, and gender-matched C57BL/6J (wild-type, WT) control mice at postnatal day 30, 4 months, and 16 months of age. We found the following: (1) region-specific and age-dependent synapse loss in aged WT mice that was not observed inC3KO mice; (2) age-dependent neuron loss in hippocampal CA3 (but not in CA1) that followed synapse loss in aged WT mice, neither of which were observed in agedC3KO mice; and (3) significantly enhanced LTP and cognition and less anxiety in agedC3KO mice compared with aged WT mice. Importantly, CA3 synaptic puncta were similar between WT andC3KO mice at P30. Together, our results suggest a novel and prominent role for complement protein C3 in mediating aged-related and region-specific changes in synaptic function and plasticity in the aging brain.SIGNIFICANCE STATEMENTThe complement cascade, part of the innate immune response to remove pathogens, also plays a role in synaptic refinement during brain development by the removal of weak synapses. We investigated whether complement C3, a central component, affects synapse loss during aging. Wild-type (WT) andC3knock-out (C3KO) mice were examined at different ages. The mice were similar at 1 month of age. However, with aging, WT mice lost synapses in specific brain regions, especially in hippocampus, an area important for memory, whereasC3KO mice were protected. AgedC3KO mice also performed better on learning and memory tests than aged WT mice. Our results suggest that complement C3, or its downstream signaling, is detrimental to synapses during aging.

Tauopathies are a class of neurodegenerative diseases characterized by the presence of hyperphosphorylated and aggregated tau pathology in neuronal and glial cells. Though the ratio of neuronal and glial tau aggregates varies across diseases, glial tau aggregates can populate the same degenerating brain regions as neuronal tau aggregates. While much is known about the deleterious consequences of tau pathology in neurons, the relative contribution of glial tau pathology to these diseases is less clear. Recent studies using a number of model systems implicate glial tau pathology in contributing to tauopathy pathogenesis. This review aims to highlight the functional consequences of tau overexpression in glial cells and explore the potential contribution of glial tau pathology in the pathogenesis of neurodegenerative tauopathies.

Although alterations in glial structure and function commonly accompany death of neurons in neurodegenerative diseases, the role glia play in modulating neuronal loss is poorly understood. We have created a model of Alexander disease inDrosophilaby expressing disease-linked mutant versions of glial fibrillary acidic protein (GFAP) in fly glia. We find aggregation of mutant human GFAP into inclusions bearing the hallmarks of authentic Rosenthal fibers. We also observe significant toxicity of mutant human GFAP to glia, which is mediated by protein aggregation and oxidative stress. Both protein aggregation and oxidative stress contribute to activation of a robust autophagic response in glia. Toxicity of mutant GFAP to glial cells induces a non-cell-autonomous stress response and subsequent apoptosis in neurons, which is dependent on glial glutamate transport. Our findings thus establish a simple genetic model of Alexander disease and further identify cellular pathways critical for glial-induced neurodegeneration.

A subset of neurodegenerative tauopathies is characterized by abundant filamentous inclusions of hyperphosphorylated tau in both neurons and glia. Although the contribution of neuronal tau to behavioral changes and neuronal loss in neurodegenerative diseases has been studied extensively, the functional consequences of tau deposition in glial cells have been less well characterized. To investigate the role of abnormal tau accumulation and aggregation in glial cells, we created aDrosophilamodel of glial tauopathy by expressing human wild-type tau in adult fly glial cells. Glial expression of tau resulted in robust aggregation of phosphorylated tau into fibrillary inclusions similar to human glial tangles. Tangle formation was accompanied by shortened lifespan and age-dependent apoptotic cell death of both glia and neurons. Genetic manipulation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling modified toxicity of glial tau. We also identified a synergistic interaction of combined tau expression in neurons and glial cells. In summary, we present a genetically tractable model of glial fibrillary tau tangle formation and identify JAK/STAT signaling as mediating the death of both glia and neurons in this model.

Although a number of studies have demonstrated proliferation of nonneoplastic astrocytes in experimental animal models, the proliferative potential of human astrocytes has not been well defined. Using double-label immunohistochemistry, we identified proliferating cells with the proliferation marker MIB-1 and astrocytes with glial fibrillary acidic protein staining in human biopsy and autopsy tissue. MIB-1 labeling of astrocytes was monitored in a variety of conditions containing significant numbers of reactive astrocytes, including infections, arteriovenous malformations, demyelinating lesions, metastatic tumors, and long-standing gliosis. Twenty-nine of a total of 54 cases showed no evidence of astrocyte-specific MIB-1 labeling despite prominent reactive changes. An average proliferation rate of 0.9% was present in the remaining 25 cases. Labeling indices were highest in infectious conditions and acute demyelinating lesions. We also examined astrocyte proliferation in 5 cases of progressive multifocal leukoencephalopathy. Astrocytic labeling indices were notably elevated in these cases, with an average labeling index of 5.8%. We conclude that low, but appreciable, astrocytic proliferation may occur in nonneoplastic human astrocytes. These findings have implications for astrocyte function in the normal and disease states and for the diagnostic distinction between reactive lesions and low-grade astrocytic neoplasms.

Neurofibromatosis type 1 is a chronic multisystemic genetic disorder that results from loss of function in the neurofibromin protein. Neurofibromin may regulate metabolism, though the underlying mechanisms remain largely unknown. Here we show that neurofibromin regulates metabolic homeostasis in Drosophila via a discrete neuronal circuit. Loss of neurofibromin increases metabolic rate via a Ras GAP-related domain-dependent mechanism, increases feeding homeostatically, and alters lipid stores and turnover kinetics. The increase in metabolic rate is independent of locomotor activity, and maps to a sparse subset of neurons. Stimulating these neurons increases metabolic rate, linking their dynamic activity state to metabolism over short time scales. Our results indicate that neurofibromin regulates metabolic rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may represent a pathophysiological mechanism in neurofibromatosis type 1, and provide a platform for investigating the cellular role of neurofibromin in metabolic homeostasis.