Biology subjects

Heppner, F. L.

Publications and source records attributed to Heppner, F. L..

11 recordsLinked to original sources

bioRxiv2025

Altered Brain Energy Metabolism in the APPPS1 Alzheimer's Model during anesthesia: Integration of Experimental Data and In Silico Modeling

BackgroundSynaptic transmission and network activity rely on high ATP turnover. Impairments in cerebral energy metabolism are increasingly recognized as central in aging and Alzheimers disease (AD) pathogenesis. Elderly patients and patients with AD are also at elevated risk for perioperative neurological complications, including post-operative delirium and further cognitive deterioration. However, the interaction between metabolic vulnerability and anesthetic exposure remains incompletely understood. MethodsWe investigated cortical metabolic responses and potassium homeostasis in acute brain slices from wild-type (WT) and AD-like APPPS1 transgenic mice, which were either exposed to isoflurane or left untreated. Glia cells were assessed by staining microglia and astrocytes. Measurements of the cerebral metabolic rate of oxygen (CMRO2), extracellular potassium dynamics, and proteomic profiling were integrated with computational modeling to assess oxidative metabolism and anesthetic effects under different conditions. ResultsAPPPS1 mice exhibited reduced CMRO2 and attenuated neuronal activity compared to age-matched WT controls, showing sex-specific differences. Proteomic analysis revealed the downregulation of key mitochondrial and glycolytic enzymes, indicating an impaired ATP- generating capacity. Exposure to isoflurane further suppressed CMRO2, with a more pronounced effect in the APPPS1 brain tissue, while glia cells exhibited no acute changes. Additionally, isoflurane exacerbated deficits in extracellular potassium ([K]) clearance, highlighting impaired ion homeostasis under anesthetic challenge. ConclusionsOur findings demonstrate that AD-like pathology in APPPS1 mice is associated with a significant decline in oxidative metabolism and ATP availability. These deficits are exacerbated by anesthetic exposure, contributing to impaired potassium regulation. This suggests that diminished metabolic flexibility may underlie increased anesthetic vulnerability and postoperative complications in AD.

neuroscience↗

bioRxiv2025

RNA promotes synapsin coacervation and modulates local translation

Condensates at synapses organize synaptic vesicle (SV) clusters and are essential for efficient neurotransmitter release. While it is established that RNA granules traffic along the axons, the function of RNA at the presynapse remains unclear. Here, we uncover a direct structural role of coding RNAs in organizing presynaptic condensates by focusing on SV clusters, condensates between synapsin-1 and lipid vesicles, a defining feature of nerve terminals. Using in vitro reconstitution systems, we show that RNA drives synapsin-1 coacervation, with bias toward structured RNAs being more effective at promoting phase transitions. The importance of RNA was confirmed in living synapses, where acute disruption of native RNA induces a dispersion of SVs and synapsin. Conversely, ectopically expressed SV-like condensates have the ability to recruit the translational machinery. The microscopy-based in vitro translation assay demonstrates increased translation efficiency within synapsin-1/RNA condensates. Together, our work indicates a novel structural role of RNAs in modulating SV condensates.

cell biology↗

bioRxiv2023

Aβ Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer's Disease

We report a highly significant correlation between human Alzheimers disease (AD) brain proteome changes and those in CRND8 APP695NL/F transgenic mice. Comparing protein changes observed in the CRND8 mice with co-expression networks derived from human Alzheimers disease (AD), reveals both conserved and divergent module changes. Many proteins in the most highly conserved module (M42, matrisome) accumulate in plaques, cerebrovascular amyloid (CAA), dystrophic neuronal processes, or a combination thereof. Overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), in CRND8 mice brains leads to increased accumulation of A{beta} in plaques and in blood vessels; further, recombinant MDK and PTN enhance A{beta} aggregation into amyloid structures. Multiple M42 proteins bind to fibrillar A{beta}42 and a non-human amyloid fibril in vitro. Supporting this binding data, MDK and PTN co-accumulate with transthyretin (TTR) amyloid in the heart. Notably, our findings establish that proteomic changes in modules observed in human AD brains define an A{beta} amyloid "responsome" that is well conserved from mouse models to humans. Further, distinct amyloid structures appear to serve as scaffolds, facilitating the co-accumulation of proteins with signaling functions, and this co-accumulation may contribute to downstream pathological sequalae. Overall, this contextualized understanding of proteomic changes and their interplay with amyloid deposition provides valuable insights into the complexity of AD pathogenesis and potential biomarkers and therapeutic targets.

neuroscience↗

bioRxiv2022

Neuroprotective tissue adaptation induced by IL-12 attenuates CNS inflammation

IL-12 is a well-established driver of type 1 immune responses. Paradoxically, in several autoimmune conditions including neuroinflammation, IL-12 reduces pathology and exhibits regulatory properties. Yet, the mechanism and the involved cellular players behind this immune regulation remain elusive. To identify the IL-12-responsive elements which prevent immunopathology, we generated mouse models lacking a functional IL-12 receptor either in all cells or in specific populations within the immune or central nervous system (CNS) compartments, and induced experimental autoimmune encephalomyelitis (EAE), which models human Multiple Sclerosis (MS). This revealed that the CNS tissue-protective features of IL-12 are mediated by cells of the neuroectoderm, and not immune cells. Importantly, sections of brain from patients with MS show comparable patterns of expression, indicating parallel mechanisms in humans. By combining spectral flow cytometry, bulk and single-nucleus RNA sequencing, we uncovered an IL-12-induced neuroprotective adaption of the neuroectoderm critically involved in maintaining CNS tissue integrity during inflammation.

immunology↗

bioRxiv2021

Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer's disease mouse model

Deposition of amyloid beta (A{beta}) along with glia cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimers disease (AD). In recent years, impairment of autophagy has been found to be another important feature, contributing to AD progression and aging. Therefore, we assessed the effect of the autophagy activator Spermidine, a small body-endogenous polyamine often used as dietary supplement and known to promote longevity, on glia cell-mediated neuroinflammation. Spermidine reduced TLR3- and TLR4- mediated inflammatory processes in microglia and astrocytes by decreasing cytotoxicity, inflammasome activity and NF-{kappa}B signaling. In line with these anti-inflammatory effects, oral treatment of the amyloid prone AD-like APPPS1 mice with Spermidine reduced neuroinflammation and neurotoxic soluble A{beta}. Mechanistically, single nuclei sequencing revealed microglia as one of the main targets of Spermidine treatment, with increased expression of genes implicated in cell motility and phagocytosis. Thus, Spermidine provides a promising therapeutic potential to target glia cells in AD progression.

neuroscience↗

bioRxiv2021

Diverse but unique astrocytic phenotypes during embryonic stem cell differentiation, culturing and aging

Astrocytes are resident glia cells of the central nervous system (CNS) that play complex and heterogeneous roles in brain development, homeostasis and disease. Since their vast involvement in health and disease is becoming increasingly recognized, suitable and reliable tools for studying these cells in vivo and in vitro are of utmost importance. One of the key challenges hereby is to adequately mimic their context-dependent in vivo phenotypes and functions in vitro. To better understand the spectrum of astrocytic variations in defined settings we performed a side-by-side-comparison of embryonic stem cell (ESC)-derived astrocytes as well as primary neonatal and adult astrocytes, revealing major differences on a functional and transcriptomic level, specifically on proliferation, migration, calcium signaling and cilium activity. Our results highlight the need to carefully consider the choice of astrocyte origin and phenotype with respect to age, isolation and culture protocols based on the respective biological question.

neuroscience↗

bioRxiv2021

The neuroinflammatory interleukin-12 signaling pathway drives Alzheimer's disease-like pathology by perturbing oligodendrocyte survival and neuronal homeostasis

Alzheimers disease (AD) is characterized by deposition of pathological amyloid-{beta} (A{beta}) and tau protein aggregates and involves chronic neuroinflammation, ultimately leading to neurodegeneration and cognitive decline. Central in AD-related neuroinflammation is the proinflammatory interleukin-12 (IL-12)/IL-23 signaling pathway whose inhibition has been shown to attenuate pathology and cognitive defects in AD-like mice. In order to explore which cell types are involved in this neuroinflammatory cascade, we used single-nuclei RNA sequencing in AD-like APPPS1 mice lacking or harboring IL-12/IL-23 signaling. We found Il12b transcripts encoding the common p40 subunit of IL-12/IL-23 signaling to be expressed preferentially, but not exclusively, in microglia in an AD-specific manner. In contrast, transcripts for the other subunits of the IL-12 signaling pathway were expressed constitutively in neurons and oligodendrocytes irrespective of AD pathology, while transcripts for IL-23 were almost undetectable. Notably, genetic ablation of IL-12/IL-23 signaling did not affect the inflammatory gene expression profile of the AD-specific disease associated microglia (DAM), but reversed the loss of mature myelin-producing oligodendrocytes and alterations in neuronal homeostasis in APPPS1 mice. Taken together, our results reveal that IL-12, but not IL-23 is the main driver of AD-specific IL-12/IL-23 neuroinflammation, which alters neuronal and oligodendrocyte functions. Given that drugs targeting IL-12 already exist, our data may foster first clinical trials in AD subjects using this novel neuroimmune target.

neuroscience↗

bioRxiv2021

Preparation of large-scale digitization samples for automated electron microscopy of tissue and cell ultrastructure

Manual selection of targets in experimental or diagnostic samples by transmission electron microscopy (TEM), based on single overview and detail micrographs, has been time- consuming and susceptible to bias. Substantial information and throughput gain may now be achieved by automated acquisition of virtually all structures in a given EM section. Resulting datasets allow convenient pan-and-zoom examination of tissue ultrastructure with preserved microanatomical orientation. The technique is, however, critically sensitive to artifacts in sample preparation. We therefore established a methodology to prepare large-scale digitization samples (LDS) designed to acquire entire sections free of obscuring flaws. For evaluation, we highlight the supreme performance of scanning EM in transmission mode compared to other EM technology. The use of LDS will substantially facilitate access to EM data for a broad range of applications.

neuroscience↗

bioRxiv2020

The autophagy activator Spermidine ameliorates Alzheimer's disease pathology and neuroinflammation in mice

Deposition of amyloid beta (A{beta}) and phosphorylated Tau along with microglia- and astrocyte-mediated neuroinflammation are prominent pathogeneic features of Alzheimers Disease (AD). In recent years, impairment of autophagy has also been shown to contribute to AD progression. Here, we provide evidence that oral treatment of amyloid-prone AD-like APPPS1 mice with the autophagy activator Spermidine, a small body-endogenous polyamine often used as dietary supplement, decreased neuroinflammation and reduced neurotoxic soluble A{beta} at both early and late stages of AD. Mechanistically, Spermidine induced autophagy in microglia as well as in astrocytes, which subsequently impacted TLR3- and TLR4-mediated inflammatory processes by decreasing cytotoxicity, inflammasome activity and NF-{kappa}B signalling. Our data highlight that autophagy targets the inflammatory response of glial cells and emphasize the potential of orally administered autophagy-activating drugs such as Spermidine to interfere with AD progression.

neuroscience↗

bioRxiv2020

Olfactory transmucosal SARS-CoV-2 invasion as port of Central Nervous System entry in COVID-19 patients

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease presenting with fever, cough, and often pneumonia. Moreover, thromboembolic events throughout the body including the central nervous system (CNS) have been described. Given first indication for viral RNA presence in the brain and cerebrospinal fluid and in light of neurological symptoms in a large majority of COVID-19 patients, SARS-CoV-2-penetrance of the CNS is likely. By precisely investigating and anatomically mapping oro- and pharyngeal regions and brains of 32 patients dying from COVID-19, we not only describe CNS infarction due to cerebral thromboembolism, but also demonstrate SARS-CoV-2 neurotropism. SARS-CoV-2 enters the nervous system via trespassing the neuro-mucosal interface in the olfactory mucosa by exploiting the close vicinity of olfactory mucosal and nervous tissue including delicate olfactory and sensitive nerve endings. Subsequently, SARS-CoV-2 follows defined neuroanatomical structures, penetrating defined neuroanatomical areas, including the primary respiratory and cardiovascular control center in the medulla oblongata.

neuroscience↗

bioRxiv2019

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

Although human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs have been suggested to be involved in neurological disorders, little is known about their biological function and pathophysiological relevance. HERV-K(HML-2) comprises evolutionarily young proviruses transcribed in the brain. We report that RNA derived from an HERV-K(HML-2) env gene region binds to the human RNA-sensing Toll-like receptor (TLR) 8, activates human TLR8, as well as murine Tlr7, and causes neurodegeneration through TLR8 and Tlr7 in neurons and microglia. HERV-K(HML-2) RNA introduced extracellularly into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimers disease (AD), resulted in neurodegeneration. Tlr7-deficient mice were protected against neurodegenerative effects, but were re-sensitized towards HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Accordingly, transcriptome datasets of human brain samples from AD patients revealed a specific correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from AD individuals compared to controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for human TLR8 and murine Tlr7 and imply a functional contribution of specific human endogenous retroviral transcripts to neurodegenerative processes such as AD.

neuroscience↗