Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer's disease.

Reduction of amyloid beta (Aß) has been shown to be effective in treating Alzheimer's disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aß is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aß in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aß production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aß production could be a promising therapeutic strategy for treating AD.

The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration.

Complement overactivation mediates microglial synapse elimination in neurological diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but how complement activity is regulated in the brain remains largely unknown. We identified that the secreted neuronal pentraxin Nptx2 binds complement C1q and thereby regulates its activity in the brain. Nptx2-deficient mice show increased complement activity, C1q-dependent microglial synapse engulfment, and loss of excitatory synapses. In a neuroinflammation culture model and in aged TauP301S mice, adeno-associated virus (AAV)-mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss. Analysis of human cerebrospinal fluid (CSF) samples from a genetic FTD cohort revealed reduced concentrations of Nptx2 and Nptx2-C1q protein complexes in symptomatic patients, which correlated with elevated C1q and activated C3. Together, these results show that Nptx2 regulates complement activity and microglial synapse elimination in the brain and that diminished Nptx2 concentrations might exacerbate complement-mediated neurodegeneration in patients with FTD.

Optogenetic polymerization and assembly of electrically functional polymers for modulation of single-neuron excitability.

Ionic conductivity and membrane capacitance are two foundational parameters that govern neuron excitability. Conventional optogenetics has emerged as a powerful tool to temporarily manipulate membrane ionic conductivity in intact biological systems. However, no analogous method exists for precisely manipulating cell membrane capacitance to enable long-lasting modulation of neuronal excitability. Genetically targetable chemical assembly of conductive and insulating polymers can modulate cell membrane capacitance, but further development of this technique has been hindered by poor spatiotemporal control of the polymer deposition and cytotoxicity from the widely diffused peroxide. We address these issues by harnessing genetically targetable photosensitizer proteins to assemble electrically functional polymers in neurons with precise spatiotemporal control. Using whole-cell patch-clamp recordings, we demonstrate that this optogenetic polymerization can achieve stepwise modulation of both neuron membrane capacitance and intrinsic excitability. Furthermore, cytotoxicity can be limited by controlling light exposure, demonstrating a promising new method for precisely modulating cell excitability.

Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models.

Microglia and complement can mediate neurodegeneration in Alzheimer's disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in TauP301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in TauP301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte-synapse association and decreased astrocytic and microglial synapses engulfment in TauP301S mice and rescued synapse density. Finally, in an AD mouse model that combines ß-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.

Don't know what you got till it's gone: microglial depletion and neurodegeneration.

In the central nervous system, immunologic surveillance and response are carried out, in large part, by microglia. These resident macrophages derive from myeloid precursors in the embryonic yolk sac, migrating to the brain and eventually populating local tissue prior to blood-brain barrier formation. Preserved for the duration of lifespan, microglia serve the host as more than just a central arm of innate immunity, also contributing significantly to the development and maintenance of neurons and neural networks, as well as neuroregeneration. The critical nature of these varied functions makes the characterization of key roles played by microglia in neurodegenerative disorders, especially Alzheimer's disease, of paramount importance. While genetic models and rudimentary pharmacologic approaches for microglial manipulation have greatly improved our understanding of central nervous system health and disease, significant advances in the selective and near complete in vitro and in vivo depletion of microglia for neuroscience application continue to push the boundaries of research. Here we discuss the research efficacy and utility of various microglial depletion strategies, including the highly effective CSF1R inhibitor models, noteworthy insights into the relationship between microglia and neurodegeneration, and the potential for therapeutic repurposing of microglial depletion and repopulation.

The Dichotomous Role of Extracellular Vesicles in the Central Nervous System.

Extracellular vesicles (EVs) are important mediators of intercellular communication. Interest in the role of central nervous system (CNS)-derived EVs has been increasing; however, some skepticism of their importance has persisted because many aspects of their biology remain elusive. This ambiguity is largely due to technical barriers that hamper our ability to achieve a comprehensive understanding of their molecular components and mechanisms responsible for their transmission and uptake. However, accumulating evidence supports the notion that EVs play important roles in basic physiological processes within the CNS during neurodevelopment and synaptic plasticity. Interestingly, EVs also act to spread toxic polypeptides in neurodegenerative diseases. Developing a more profound understanding of the role that EVs play in the CNS could lead to the identification of biomarkers and potential vehicles for drug delivery. Here we highlight our current understanding of CNS EVs and summarize our current understanding of their complex role in the CNS.

Neuroinflammation drives APOE genotype-dependent differential expression of neprilysin.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by the deposition of amyloid-beta (Aß) plaques and widespread neuroinflammation. While the cause of AD remains unknown, multiple factors likely contribute to the disease, including heart disease, diabetes, previous head injury, as well as a number of genetic determinants. Inheritance of the apolipoprotein (APOE) ε4 allele represents the strongest genetic risk factor for development of AD, driving pathogenesis and increasing overall disease severity. APOE has long been recognized as a key regulator of cholesterol homeostasis, although a greater appreciation now exists for its role in various innate immune system processes. Indeed, APOE modulates inflammatory environments in brain in large part by altering gene expression profiles in glia, important mediators of immunity in the CNS. While the association between APOE and AD was first observed nearly three decades ago, the mechanism by which APOE ε4 influences the etiology and pathophysiology of AD is not well characterized. Overwhelming data supports the hypothesis that APOE ε4 dysregulates central amyloid metabolism by an undetermined molecular mechanism, thus laying the foundation for disease. A host of amyloid-degrading enzymes (ADEs) regulate Aß accumulation in brain, and therefore represent valuable therapeutic targets. Neprilysin (NEP), a metalloendopeptidase expressed by activated microglia and astrocytes, is a broad-spectrum ADE able to degrade a variety of Aß species. Here we describe in vivo and in vitro experiments designed to investigate the potential for APOE genotype to differentially regulate glial NEP in brain under neuroinflammatory conditions. Our results provide a novel mechanism by which APOE genotype-dependent differential expression of NEP by glia during neuroinflammation may contribute to AD pathogenesis.