Biology subjects

Malm, T.

Publications and source records attributed to Malm, T..

25 records · Page 2Linked to original sources

bioRxiv2022

Microglial amyloid beta clearance is driven by PIEZO1 channels

BackgroundMicroglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimers disease (AD), toxic amyloid beta (A{beta}) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of A{beta}. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia have been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored. MethodsHere we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC) -derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and A{beta} pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations. ResultsWe show that PIEZO1 orchestrates A{beta} clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. A{beta} inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in A{beta} clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single cell datasets. ConclusionThese results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated A{beta} burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=176 HEIGHT=200 SRC="FIGDIR/small/484831v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@832eadorg.highwire.dtl.DTLVardef@6d8719org.highwire.dtl.DTLVardef@c09740org.highwire.dtl.DTLVardef@9fa85_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

isomiRs-specific differential expression is the rule, not the exception: Are we missing hundreds of species in microRNA analysis?

MicroRNAs (miRNAs) are small RNA molecules that act as regulators of gene expression through targeted mRNA degradation. They are involved in many biological and pathophysiological processes and are widely studied as potential biomarkers and therapeutics agents for human diseases, including cardiovascular disorders. Recently discovered isoforms of miRNAs (isomiRs) exist in high quantities and are very diverse. Despite having few differences with their corresponding reference miRNAs, they display specific functions and expression profiles, across tissues and conditions. However, they are still overlooked and understudied, as we lack a comprehensive view on their condition-specific regulation and impact on differential expression analysis. Here, we show that isomiRs can have major effects on differential expression analysis results, as their expression is independent of their host miRNA genes or reference sequences. We present two miRNA-seq datasets from human umbilical vein endothelial cells, and assess isomiR expression in response to senescence and compartment-specificity (nuclear/cytosolic) under hypoxia. We compare three different methods for miRNA analysis, including isomiR-specific analysis, and show that ignoring isomiRs induces major biases in differential expression. Moreover, isomiR analysis permits higher resolution of complex signal dissection, such as the impact of hypoxia on compartment localization, and differential isomiR type enrichments between compartments. Finally, we show important distribution differences across conditions, independently of global miRNA expression signals. Our results raise concerns over the quasi exclusive use of miRNA reference sequences in miRNA-seq processing and experimental assays. We hope that our work will guide future isomiR expression studies, which will correct some biases introduced by golden standard analysis, improving the resolution of such assays and the biological significance of their downstream studies.

bioinformatics↗

bioRxiv2021

Alzheimer's disease alters astrocytic functions related to neuronal support andtranscellular internalization of mitochondria

Under physiological conditions in vivo astrocytes internalize and degrade neuronal mitochondria in a process called transmitophagy. Mitophagy is widely reported to be impaired in neurodegeneration but it is unknown whether and how transmitophagy is altered in Alzheimers disease (AD). Here we report that the internalization and degradation of neuronal mitochondria are significantly increased in astrocytes isolated from aged AD mouse brains. We also demonstrate for the first time a similar phenomenon between human neurons and AD astrocytes, and in murine hippocampi in vivo. The results suggest the involvement of S100a4 in impaired mitochondrial transfer between neurons and aged AD astrocytes. Significant increases in the mitophagy regulator Ambra1 were observed in the aged AD astrocytes. These findings demonstrate altered neuron-supporting functions of aged AD astrocytes and provide a starting point for studying the molecular mechanisms of transmitophagy in AD.

neuroscience↗

bioRxiv2021

Subacute Inhalation of Ultrafine Particulate Matter Triggers Inflammation Without Altering Amyloid Beta Load in 5xFAD mice.

Epidemiological studies reveal that air pollution exposure may exacerbate neurodegeneration. Ultrafine particles (UFPs) are pollutants that remain unregulated in ambient air by environmental agencies. Due to their small size (<100nm), UFPs have the most potential to cross the bodily barriers and thus impact the brain. However, little information exists about how UFPs affect brain function. Alzheimers disease (AD) is the most common form of dementia, which has been linked to air pollutant exposure, yet limited information is available on the mechanistic connection between them. This study aims to decipher the effects of UFPs in the brain and periphery using the 5xFAD mouse model of AD. In our study design, AD mice and their wildtype littermates were subjected to 2-weeks inhalation exposure of UFPs in a whole-body chamber. That subacute exposure did not affect the blood-brain barrier integrity or amyloid-beta accumulation. However, when multiple cytokines were analyzed, we found increased levels of proinflammatory cytokines in the brain and periphery, with a predominant alteration of interferon-gamma in response to UFP exposure in both genotypes. Following exposure, mitochondrial superoxide dismutase was significantly upregulated only in the 5xFAD hippocampi, depicting oxidative stress induction in the exposed AD mouse group. These data demonstrate that short-term exposure to inhaled UFPs induces inflammation without affecting amyloid-beta load. This study provides a better understanding of adverse effects caused by short-term UFP exposure in the brain and periphery, also in the context of AD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/459017v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@479511org.highwire.dtl.DTLVardef@18bc59aorg.highwire.dtl.DTLVardef@15a0240org.highwire.dtl.DTLVardef@49f911_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Microglia orchestrate neuronal activity in brain organoids

Human stem cell-derived brain organoids provide a physiologically relevant in vitro 3D brain model for studies of neurological development that are unique to the human nervous system. Prior studies have reported protocols that support the maturation of microglia from mesodermal progenitors leading to innately developing microglia within the organoids. However, although microglia are known to support neuronal development in rodents, none of the previous studies have reported what is the impact of microglia on neuronal growth and maturation in human brain organoids. Here we show that incorporating microglial progenitors into the developing organoid supports neuronal maturation, the emergence of neurons capable of firing repetitive action potentials and the appearance of synaptic and neuronal bursting activity. Immunocompetent organoids enable experimental strategies for interrogating fundamental questions on microglial and neuronal diversity and function during human brain development.

neuroscience↗

bioRxiv2020

Disease specific alterations in the olfactory mucosa of patients with Alzheimer's disease

Olfactory dysfunction manifests early in several neurodegenerative disorders. Olfaction is orchestrated by olfactory mucosal cells located in the upper nasal cavity. However, it is unclear how this tissue reflects key neurodegenerative features in Alzheimers disease. Here we report that Alzheimers disease olfactory mucosal cells obtained from live individuals secrete toxic amyloid-beta. We detail cell-type-specific gene expression patterns, unveiling 147 differentially expressed disease-associated genes compared to the cognitively healthy controls, and 5 distinct populations in globose basal cell -, myofibroblast-, and fibroblast/ stromal - like cells in vitro. Overall, coordinated alteration of RNA and protein metabolism, inflammatory processes and signal transduction were observed in multiple cell populations, suggesting a key role in pathophysiology. Our results demonstrate the potential of olfactory cell cultures in modelling Alzheimers disease advocate their use for diagnostic purposes. Moreover, for the first time we provide single cell data on olfactory mucosa in Alzheimers disease for investigating molecular and cellular mechanisms associated with the disease.

neuroscience↗

bioRxiv2020

The role of the meningeal lymphatic system in local inflammation and trigeminal nociception implicated in migraine pain

BackgroundA system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in cleaning the brain via cerebral fluid drainage. As meninges are the origin site of migraine pain, we hypothesized that malfunctioning of the lymphatic system should affect the local trigeminal nociception. To test this hypothesis, we studied nociceptive and inflammatory mechanisms in the meninges of K14-VEGFR3-Ig mice lacking the meningeal lymphatic system. MethodsWe recorded the spiking activity of meningeal afferents and estimated the local mast cells infiltration, calcitonin gene-related peptide (CGRP) and cytokine levels (basal and stimulated), as well as the dural trigeminal innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT). ResultsWe found that the meningeal level of CGRP and of the pro-inflammatory cytokines IL12-p70 and TNF (implicated in migraine) were reduced in the meninges of K14 mice. On the contrary, in the meninges of K14 mice, we found an increased level of the mast cell activator MCP-1 and, consistently, a larger number of dural mast cells. The other migraine-related pro-inflammatory cytokines did not differ between the two genotypes. The patterns of trigeminal innervation in meninges remained unchanged and we did not observe alterations in basal or ATP-induced nociceptive firing in the meningeal afferents. ConclusionsIn summary, the lack of meningeal lymphatic system does not induce migraine-like nociceptive state per se, but leads to a new balance between pro- and antiinflammatory factors implicated in migraine mechanisms.

neuroscience↗