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APOE is the strongest genetic risk factor for late-onset Alzheimer’s disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here we show that overexpressing an apoE metabolic receptor LDLR (low-density lipoprotein receptor) in P301S tauopathy mice markedly reduces brain apoE, and ameliorates tau pathology and neurodegeneration. LDLR overexpression (OX) in microglia cell-autonomously downregulates microglial Apoe expression, and is associated with suppressed microglial activation as in apoE-deficient microglia. Both apoE-deficiency and LDLR-OX strongly drive microglial immunometabolism towards enhanced catabolism over anabolism, whereas LDLR-overexpressing microglia also uniquely upregulate specific ion channels and neurotransmitter receptors upon activation. ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells (OPCs), and show greater preservation of myelin integrity under neurodegenerative conditions. They also show less reactive astrocyte activation in the setting of tauopathy.

Ising et al. report expression of anti-tau scFvs in the brain of a mouse model of tauopathy by AAV-mediated gene transfer. Treated mice show markedly decreased tau hyperphosphorylation and detergent-soluble tau species. Therefore, the Fc domain is not required to mediate effects in tauopathy., Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the Fc domain of HJ8.5 is required for the therapeutic effect, we engineered single-chain variable fragments (scFvs) derived from HJ8.5 with variable linker lengths, all specific to human tau. Based on different binding properties, we selected two anti-tau scFvs and tested their efficacy in vivo by adeno-associated virus–mediated gene transfer to the brain of P301S-tg mice. The scFvs significantly reduced levels of hyperphosphorylated, aggregated tau in brain tissue of P301S-tg mice, associated with a decrease in detergent-soluble tau species. Interestingly, these mice showed substantial levels of scFvs in the cerebrospinal fluid without significant effects on total extracellular tau levels. Therefore, our study provides a novel strategy for anti-tau immunotherapeutics that potentially limits a detrimental proinflammatory response.

APOE is the strongest genetic risk factor for late-onset Alzheimer’s disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here we show that overexpressing a low-density lipoprotein receptor (LDLR) transgene in P301S tau transgenic mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. ApoE specifically interacts with a high-molecular-weight tau species, and highly correlates with phospho-tau and insoluble tau levels. Microglial expression of the LDLR transgene reduces intracellular apoE and is associated with less microglial activation. snRNA-seq analysis of apoE-deficient or LDLR-overexpressing brains reveals that apoE deficiency drives microglial catabolism and increases the oligodendrocyte progenitor cell population. LDLR overexpression shares overlapping mechanisms, but uniquely upregulates microglial expression of specific ion channels and neurotransmitter receptors in tauopathy. A subset of disease-associated astrocytes with both neuroprotective and neurotoxic gene signatures is also identified.

International audience; Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline1. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release2. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice3, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer's disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation.

Summary: The cellular responses induced by mitochondrial dysfunction remain elusive. Intrigued by the lack of almost any glomerular phenotype in patients with profound renal ischemia, we comprehensively investigated the primary sources of energy of glomerular podocytes. Combining functional measurements of oxygen consumption rates, glomerular metabolite analysis, and determination of mitochondrial density of podocytes in vivo, we demonstrate that anaerobic glycolysis and fermentation of glucose to lactate represent the key energy source of podocytes. Under physiological conditions, we could detect neither a developmental nor late-onset pathological phenotype in podocytes with impaired mitochondrial biogenesis machinery, defective mitochondrial fusion-fission apparatus, or reduced mtDNA stability and transcription caused by podocyte-specific deletion of Pgc-1α, Drp1, or Tfam, respectively. Anaerobic glycolysis represents the predominant metabolic pathway of podocytes. These findings offer a strategy to therapeutically interfere with the enhanced podocyte metabolism in various progressive kidney diseases, such as diabetic nephropathy or focal segmental glomerulosclerosis (FSGS). : Glomerular podocytes form the third and most outer layer of the kidney filtration barrier responsible for restricting the passage of proteins into the urine. Brinkkoetter et al. show that podocyte metabolism primarily relies on anaerobic glycolysis and the fermentation of glucose to lactate. Keywords: glomerular filtration barrier, podocytes, anaerobic glycolysis, metabolomics

Mitochondrial dysfunction and alterations in energy metabolism have been implicated in a variety of human diseases. Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Here, we provide a link between PHB2 deficiency and hyperactive insulin/IGF-1 signaling. Deletion of PHB2 in podocytes of mice, terminally differentiated cells at the kidney filtration barrier, caused progressive proteinuria, kidney failure, and death of the animals and resulted in hyperphosphorylation of S6 ribosomal protein (S6RP), a known mediator of the mTOR signaling pathway. Inhibition of the insulin/IGF-1 signaling system through genetic deletion of the insulin receptor alone or in combination with the IGF-1 receptor or treatment with rapamycin prevented hyperphosphorylation of S6RP without affecting the mitochondrial structural defect, alleviated renal disease, and delayed the onset of kidney failure in PHB2-deficient animals. Evidently, perturbation of insulin/IGF-1 receptor signaling contributes to tissue damage in mitochondrial disease, which may allow therapeutic intervention against a wide spectrum of diseases.

Over the past decades, our view on neurodegenerative diseases has been mainly centered around neurons and their networks. Only recently it became evident that immunological processes arise alongside degenerating neurons, raising the question whether these represent just meaningless bystander reactions or in turn, contribute to pathogenesis and disease symptoms. When considering any effect of inflammatory events on the CNS one has to consider the site, duration and nature of immune activation. Likewise, one has to distinguish between mechanisms which directly impact the neuronal compartment and indirect mechanisms, which affect cells that are important for neuronal functioning and survival. As discussed in this review, both types of mechanisms may be present at the same time and additively or synergistically lead to neuronal demise. Inflammatory mediators released by the principle innate immune cells of the brain, microglia and astrocytes, can compromise the function and structure of neurons, thereby playing important roles in the pathogenesis of neurodegenerative diseases.

Alzheimer disease (AD) is the most common cause of dementia and is characterized by the aggregation and accumulation of two proteins in the brain, amyloid-β (Aβ) and tau. Aβ and tau begin to buildup 15-20 years before the clinical onset of AD dementia. Increasing evidence suggests that preventing or decreasing the amount of aggregated forms of both Aβ and tau in the brain can serve as potential disease-modifying treatments for AD.

The kidney filtration barrier consists of three well-defined anatomic layers comprising a fenestrated endothelium, the glomerular basement membrane (GBM) and glomerular epithelial cells, the podocytes. Podocytes are post-mitotic and terminally differentiated cells with primary and secondary processes. The latter are connected by a unique cell-cell contact, the slit diaphragm. Podocytes maintain the GBM and seal the kidney filtration barrier to prevent the onset of proteinuria. Loss of prohibitin-1/2 (PHB1/2) in podocytes results not only in a disturbed mitochondrial structure but also in an increased insulin/IGF-1 signaling leading to mTOR activation and a detrimental metabolic switch. As a consequence, PHB-knockout podocytes develop proteinuria and glomerulosclerosis and eventually loss of renal function. In addition, experimental evidence suggests that PHB1/2 confer additional, extra-mitochondrial functions in podocytes as they localize to the slit diaphragm and thereby stabilize the unique intercellular contact between podocytes required to maintain an effective filtration barrier.

Maintenance of the glomerular filtration barrier with its fenestrated endothelium, the glomerular basement membrane, and the podocytes as the outer layer, is a major prerequisite for proper renal function. Tight regulation of the balance between plasticity and rigidity of the podocytes' architecture is required to prevent the onset of glomerular disease, mainly proteinuria. The underlying cellular signaling pathways that regulate the organization of the podocytes' cytoskeleton are still a matter of controversial debate. In this study, we investigated the role of the NF-κB signaling pathway in podocyte cytoskeletal dynamics. As previously published, genetic inhibition of the NF-κB essential modulator (NEMO) in podocytes does not affect glomerular function under physiological, nonstressed conditions nor does it alter the initial podocyte response in an experimental glomerulonephritis (NTN) model (Brähler S, Ising C, Hagmann H, Rasmus M, Hoehne M, Kurschat C, Kisner T, Goebel H, Shankland SJ, Addicks K, Thaiss F, Schermer B, Pasparakis M, Benzing T, Brinkkoetter PT. Am J Physiol Renal Physiol 303: F1473–F1475, 2012). Quite the contrary, podocyte-specific NEMO null mice recovered significantly faster and did not develop glomerulosclerosis and end-stage renal failure over time. Here, we show that cytoskeletal rearrangements and increased podocyte motility following stimulation with IL-1, TNF-α, or LPS depend on NEMO. NEMO also regulates the phosphorylation of the MAP kinase ERK1/2 and suppresses the activation of RhoA following stimulation with IL-1. The migratory response and altered ERK1/2 phosphorylation is independent of NF-κB signaling as demonstrated by expression of a mutant IκB resistant to phosphorylation and degradation. In conclusion, signaling through NEMO might not only be involved in the production of NF-κB proinflammatory chemokines but also regulates podocyte dynamics independently of NF-κB, most likely through small GTPases and MAP kinases.

Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the F

In the past decade, our understanding of the role of podocytes in the function of the glomerular filtration barrier, and of the role of podocyte injury in the pathogenesis of proteinuric kidney disease, has substantially increased. Landmark genetic studies identified mutations in genes expressed by podocytes as a cause of albuminuria and nephrotic syndrome, leading to breakthrough discoveries from many laboratories. These discoveries contributed to a dramatic change in our view of the glomerular filtration barrier of the kidney and of the role of podocyte injury in the development of albuminuria and progressive kidney disease. In the past several years, studies have demonstrated that podocyte injury is a major cause of marked albuminuria and nephrotic syndrome, and have confirmed that podocytes are important for the maintenance of an intact glomerular filtration barrier. An essential role of loss of these cells in the pathogenesis of glomerulosclerosis and progressive proteinuric kidney disease has also been identified. In this Review, we discuss the importance of podocytes for the maintenance of an intact glomerular filtration barrier and their role in albumin handling.

Inflammation conveys the development of glomerular injury and is a major cause of progressive kidney disease. NF-κB signaling is among the most important regulators of proinflammatory signaling. Its role in podocytes, the epithelial cells at the kidney filtration barrier, is poorly understood. Here, we inhibited NF-κB signaling in podocytes by specific ablation of the NF-κB essential modulator (NEMO, IKKγ). Podocyte-specific NEMO-deficient mice (NEMOpko) were viable and did not show proteinuria or overt changes in kidney morphology. After induction of glomerulonephritis, both NEMOpkoand control mice developed significant proteinuria. However, NEMOpkomice recovered much faster, showing rapid remission of proteinuria and restoration of podocyte morphology. Interestingly, quantification of infiltrating macrophages, T-lymphocytes, and granulocytes at day 7 revealed no significant difference between wild-type and NEMOpko. To further investigate the underlying mechanisms, we created a stable NEMO knockdown mouse podocyte cell line. Again, no overt changes in morphology were observed. Translocation of NF-κB to the nucleus after stimulation with TNFα or IL-1 was sufficiently inhibited. Moreover, secretion of proinflammatory chemokines from podocytes after stimulation with TNFα or IL-1 was significantly reduced in NEMO-deficient podocytes and in glomerular samples obtained at day 7 after induction of nephrotoxic nephritis. Collectively, these results show that proinflammatory activity of NF-κB in podocytes aggravates proteinuria in experimental glomerulonephritis in mice. Based on these data, it may be speculated that immunosuppressive drugs may not only target professional immune cells but also podocytes directly to convey their beneficial effects in various types of glomerulonephritis.