ABSTRACT
Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.
Subject(s)
Microglia , Nucleotidyltransferases , tau Proteins , Animals , Mice , Cognition , Immunity, Innate , Interferons , MEF2 Transcription Factors/genetics , Microglia/metabolism , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolismABSTRACT
Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a TAU-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which TAU has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral TAU reduction could have similar benefits, even when initiated postnatally.
Subject(s)
Autistic Disorder , Epilepsies, Myoclonic , Epilepsy , Sudden Unexpected Death in Epilepsy , tau Proteins , Animals , Autistic Disorder/complications , Autistic Disorder/genetics , Disease Models, Animal , Epilepsies, Myoclonic/complications , Epilepsies, Myoclonic/genetics , Epilepsy/complications , Epilepsy/genetics , Epilepsy/metabolism , Epileptic Syndromes , Humans , Infant , Mice , Neurons/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Spasms, Infantile , tau Proteins/metabolismABSTRACT
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation of glycosaminoglycans (GAGs) throughout the body. Treatment of MPS II remains a considerable challenge as current enzyme replacement therapies do not adequately control many aspects of the disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that is engineered to bind to the transferrin receptor; this design facilitates receptor-mediated transcytosis of IDS across the blood-brain barrier and improves its distribution into the brain while maintaining distribution to peripheral tissues. Here we show that chronic systemic administration of ETV:IDS in a mouse model of MPS II reduced levels of peripheral and central nervous system GAGs, microgliosis, and neurofilament light chain, a biomarker of neuronal injury. Additionally, ETV:IDS rescued auricular and skeletal abnormalities when introduced in adult MPS II mice. These effects were accompanied by improvements in several neurobehavioral domains, including motor skills, sensorimotor gating, and learning and memory. Together, these results highlight the therapeutic potential of ETV:IDS for treating peripheral and central abnormalities in MPS II. DNL310, an investigational ETV:IDS molecule, is currently in clinical trials as a potential treatment for patients with MPS II.
Subject(s)
Blood-Brain Barrier/metabolism , Enzyme Replacement Therapy/methods , Iduronate Sulfatase/administration & dosage , Mucopolysaccharidosis II/drug therapy , Receptors, Transferrin/metabolism , Transport Vesicles/metabolism , Animals , Behavior, Animal/drug effects , Disease Models, Animal , Glycosaminoglycans/metabolism , Iduronate Sulfatase/genetics , Memory/drug effects , Mice , Mice, Knockout , Motor Skills/drug effects , Mucopolysaccharidosis II/genetics , Mucopolysaccharidosis II/metabolism , Mucopolysaccharidosis II/physiopathology , Phenotype , Sensory Gating/drug effects , Skeleton/drug effects , Spatial Learning/drug effects , TranscytosisABSTRACT
We tested the proposal that the C-terminal domain (CTD) of the AMPAR subunit GluA1 is required for LTP. We found that a knock-in mouse lacking the CTD of GluA1 expresses normal LTP and spatial memory, assayed by the Morris water maze. Our results support a model in which LTP generates synaptic slots, which capture passively diffusing AMPARs.
