Biology subjects

De Deyn, P. P.

Publications and source records attributed to De Deyn, P. P..

4 recordsLinked to original sources

bioRxiv2024

Age-related memory CD8 T cells induce and track Alzheimers-like neurodegeneration

Cerebral (A{beta}) plaque and (pTau) tangle deposition are hallmarks of Alzheimers disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of A{beta}/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of A{beta}/fibrillar pTau, however, appears to vary depending on the animal model used. Our prior work suggested that antigen-specific memory CD8 T ("hiT") cells act upstream of A{beta}/pTau after brain injury. Here we examine whether hiT cells influence sporadic AD-like pathophysiology upstream of A{beta}/pTau. Examining neuropathology, gene expression, and behavior in our hiT mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFN{gamma} for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. Our work is the first to identify an age-related factor acting upstream of A{beta}/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD. Significance StatementThis study changes our view of Alzheimers Disease (AD) initiation and progression. Mutations promoting cerebral beta-amyloid (A{beta}) deposition guarantee rare genetic forms of AD. Thus, the prevailing hypothesis has been that A{beta} is central to initiation and progression of all AD, despite contrary animal and patient evidence. We show that age-related T cells generate neurodegeneration with compelling features of AD in mice, with distinct T cell functions required for pathological initiation and neurodegenerative progression. Knowledge from these mice was applied to successfully predict previously unknown features of human AD and generate novel tools for its clinical management.

neuroscience↗

bioRxiv2023

Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression

Exposure to an acute stressor triggers a complex cascade of neurochemical events in the brain. However, deciphering their individual impact on stress-induced molecular changes remains a major challenge. Here we combine RNA-sequencing with selective pharmacological, chemogenetic and optogenetic manipulations to isolate the contribution of the locus coeruleus - noradrenaline (LC-NA) system to the acute stress response. We reveal that NA-release during stress exposure regulates a large and reproducible set of genes in the dorsal and ventral hippocampus via {beta}-adrenergic receptors. For a smaller subset of these genes, we show that NA release triggered by LC stimulation is sufficient to mimic the stress-induced transcriptional response. We observe these effects in both sexes, and independent of the pattern and frequency of LC activation. Using a retrograde optogenetic approach, we demonstrate that hippocampus-projecting LC neurons directly regulate hippocampal gene expression. Overall, a highly selective set of astrocyte-enriched genes emerges as key targets of LC-NA activation, most prominently several subunits of protein phosphatase 1 (Ppp1r3c, Ppp1r3d, Ppp1r3g) and type II iodothyronine deiodinase (Dio2). These results highlight the importance of astrocytic energy metabolism and thyroid hormone signaling in LC-mediated hippocampal function and offer new molecular targets for understanding how NA impacts brain function in health and disease.

neuroscience↗

bioRxiv2020

PapRIV, a BV-2 microglial cell activating quorum sensing peptide

BackgroundQuorum sensing peptides (QSPs) are bacterial peptides produced by Gram-positive bacteria to communicate with their peers in a cell-density dependent manner. These peptides do not only act as interbacterial communication signals, but can also have effects on the host. Compelling evidence demonstrates the presence of a gut-brain axis and more specifically, the role of the gut microbiota in microglial functioning. The aim of this study is to investigate microglial activating properties of a selected QSP (PapRIV) which is produced by Bacillus cereus species. MethodsGastro-intestinal transport of the peptide is investigated using the in vitro Caco-2 model while transport over the blood-brain barrier is investigated in mice using multiple time regression experiments. Microglial activation is assessed using ELISA, fluorometry, immunoblotting, qPCR and phase-contrast microscopy. In vivo plasma detection and ex vivo metabolization experiments are performed using UHPLC-MS2 and UHPLC-UV/MS, respectively. ResultsPapRIV showed in vitro activating properties of BV-2 microglia cells and was able to cross the in vitro Caco-2 cell model and pass the blood-brain barrier in vivo. In vivo peptide presence was also demonstrated in mouse plasma. The peptide caused induction of IL-6, TNF and ROS expression and increased the fraction of ameboid BV-2 microglia cells in an NF-{kappa}B dependent manner. Different metabolites were identified in serum, of which the main metabolite (DLPFEH) still remained active. ConclusionsPapRIV is thus able to cross the gastro-intestinal tract and the blood-brain barrier and shows in vitro activating properties in BV-2 microglia cells, hereby indicating a potential role of this quorum sensing peptide in gut-brain interaction.

neuroscience↗

bioRxiv2019

Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation

The locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain, regulates many fundamental brain functions, and is implicated in several neuropsychiatric diseases. Although selective manipulation of the LC is not possible in humans, studies have suggested that strong LC activation might shift network connectivity to favor salience processing. To test this hypothesis, we use a mouse model to study the impact of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term "chemo-connectomics". LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. We reveal a direct correlation between functional connectivity changes and transcript levels of alpha-1, alpha-2, and beta-1 adrenoceptors across the brain, and a positive correlation between NE turnover and functional connectivity within select brain regions. These results represent the first brain-wide functional connectivity mapping in response to LC activation, and demonstrate a causal link between receptor expression, brain states and functionally connected large-scale networks at rest. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection.

neuroscience↗