Biology subjects

Willnow, T.

Publications and source records attributed to Willnow, T..

8 recordsLinked to original sources

bioRxiv2025

Alzheimer disease risk variant rs11218343 determines functional expression of SORL1 in microglia

IntroductionRs11218343 is a non-coding variant of genome-wide significance for sporadic Alzheimers disease (AD) with one of the most protective effects known. It localizes to SORL1, encoding the AD risk factor SORLA. Still, the functional significance of rs11218343 for AD related processes remains unclear. MethodsWe used iPSC lines from donors, or genome-engineered to carry major and minor rs11218343 alleles, to study the impact of rs11218343 genotype on brain cell activities. ResultsWe show that rs11218343 uniquely controls functional expression of SORLA in microglia, with incrased receptor expression in the minor protective allele correlating with reduced pro-inflammatory responses. This anti-inflammatory effect is seen in donor iPSC lines but not in SNP-engineered isogenic lines, documenting rs11218343 to be diagnostic but not functional. DiscussionOur findings corroborate genetically defined expression levels of SORL1 in microglia as a determinant of protection from pro-inflammatory stimulation, a function encoded by a haplotype linked to rs11218343. RESEARCH IN CONTEXTO_ST_ABSSystematic reviewC_ST_ABSReviewing the literature on single nucleotide polymorphisms (SNP) showing genome-wide association with the risk of sporadic AD, we learned that prior studies identified rs11218343 as a major predictor of protection from the disease. We also learned that this SNP localizes to SORL1, encoding the AD risk factor SORLA. However, no data were available whether this SNP controls functional expression of SORLA or other AD-related proteins in brain cell types. InterpretationOur study documents that rs11218343 controls the expression of SORL1 in iPSC-derived human microglia, an effect not seen for other microglial genes. Increased expression of SORLA in the minor allele correlates with decreased inflammatory responses in this cell type. These findings suggest that the ability of SORLA to contain pro-inflammatory actions of microglia contributes to its protective effect in AD. Future directionsOur studies document rs11218343 to be diagnostic but not functional in SORL1 expression control. These findings should be corroborated in a replication cohort of donor cell lines. Also, further analyses need to identify the sequence variation in disequilibrium with rs11218343, that controls SORL1 gene transcription. Such information will be essential to mechanistically resolve the mode of action of the most protective genotype in sporadic AD known to date. HIGHLIGHTSO_LIrs11218343 predicts expressions of AD risk gene SORL1 C_LIO_LIexpression control by the linked haplotype is specific to human microglia C_LIO_LIincreased SORL1 levels with minor allele ameliorates pro-inflammatory responses C_LI

genetics↗

bioRxiv2025

A-beta-induced distress of astrocytes triggers Alzheimer disease pathology through non-canonical delta secretase activity

The importance of astrocytes for Alzheimer disease (AD) pathology is increasingly appreciated, yet the mechanisms whereby this cell type impacts neurodegenerative processes remain elusive. In a genetic mouse model with diminished astrocyte stress response, even low levels of amyloid-{beta} trigger astrocyte reactivity, resulting in brain inflammation and massive amyloid and tau pathologies. This dysfunctional response of astrocytes to amyloid-{beta} acts through activation of {delta} secretase, a stress-induced protease implicated in both amyloid and tau-related proteolytic processing. Our findings identify a failed astrocyte stress response to amyloid-{beta} as an early inducer of amyloid and tau co-morbidity, a noxious process in AD acting through a unique non-canonical secretase pathway.

neuroscience↗

bioRxiv2024

Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel

Sortilin (SORT1) is a lipoprotein receptor that shows genome-wide association with hypercholesterolemia, explained by its ability to control hepatic output of lipoproteins. Remarkably, SORT1 also shows genome-wide association with Alzheimer disease (AD) and frontotemporal lobe dementia, the most prevalent forms of age-related dementias. Yet, sortilins contribution to human brain lipid metabolism and health remains unclear. Using humanized mouse strains and iPSC-based cell models of brain lipid homeostasis, we document that sortilin mediates neuronal uptake of polyunsaturated fatty acids carried by apoE. Internalized lipids are converted into ligands for PPAR, inducing transcription profiles that enable neurons to use long-chain fatty acids as metabolic fuel. This pathway works with apoE3, but is lost with the AD risk factor apoE4, which disrupts sortilins endocytic activity. We document a role for the lipoprotein receptor sortilin in metabolic fuel choice in neurons, possibly crucial when supply with glucose is limited, as in the aging brain.

neuroscience↗

bioRxiv2022

LRP2 contributes to planar cell polarity-dependent coordination of motile cilia function

Motile cilia are protruding organelles on specialized epithelia that beat in a synchronous fashion to propel extracellular fluids. Coordination and orientation of cilia beating on individual cells and across tissues is a complex process dependent on planar cell polarity (PCP) signaling. Asymmetric sorting of PCP pathway components, essential to establish planar polarity, involves trafficking along the endocytic path, but the underlying regulatory processes remain incompletely understood. Here, we identified the endocytic receptor LRP2 as regulator of PCP component trafficking in ependyma, a multi-ciliated cell type that is involved in facilitating flow of the cerebrospinal fluid in the brain ventricular system. Lack of receptor expression in gene-targeted mice results in a failure to sort PCP core proteins to the anterior or posterior cell side and, consequently, in the inability to coordinate cilia arrangement and to aligned beating (loss of rotational and translational polarity). LRP2 deficiency coincides with a failure to sort NHERF1, a cytoplasmic LRP2 adaptor to the anterior cell side. As NHERF1 is essential to translocate PCP core protein Vangl2 to the plasma membrane, these data suggest a molecular mechanism whereby LRP2 interacts with PCP components through NHERF1 to control their asymmetric sorting along the endocytic path. Taken together, our findings identified the endocytic receptor LRP2 as a novel regulator of endosomal trafficking of PCP proteins, ensuring their asymmetric partition and establishment of translational and rotational planar cell polarity in the ependyma.

cell biology↗

bioRxiv2022

SORLA mediates endocytic uptake of proIAPP and protects against islet amyloid deposition

Aims/ hypothesisSorting-related receptor with type A repeats (SORLA) is a neuronal sorting receptor that prevents accumulation of amyloid-beta peptides, the main constituent of senile plaques in Alzheimer disease. Recent transcriptomic studies show that SORLA transcripts are also found in pancreatic islet beta cells, yet the role of SORLA in islets is unclear so far. Based on its protective role in reducing amyloid burden in the brain, we hypothesized that SORLA may have a similar function in the pancreas, regulating islet amyloid plaque formation from islet amyloid polypeptide (IAPP). MethodsWe generated human IAPP transgenic mice lacking SORLA (hIAPP:SORLA KO) to assess the consequences of receptor deficiency for islet histopathology and function in vivo. Using both primary islet cells and established cell lines, we further investigated the molecular mechanisms whereby SORLA controls the cellular metabolism and accumulation of IAPP. ResultsLoss of SORLA activity in hIAPP:SORLA KO resulted in a significant increase in islet amyloid deposits and associated islet cell death as compared to hIAPP:SORLA WT animals expressing the receptor. Aggravated islet amyloid deposition was observed in mice fed a normal chow diet, not requiring high-fat diet feeding typically needed to induce islet amyloidosis in mouse models. Further in vitro studies showed that SORLA binds to and mediates the endocytic uptake of proIAPP, but not mature IAPP, delivering the propeptide to an endolysosomal fate. Conclusions/interpretationSORLA functions as a clearance receptor specific for proIAPP, protecting against islet amyloid deposition and associated cell death caused by IAPP.

cell biology↗

bioRxiv2021

ApoE4 disrupts interaction of sortilin with fatty acid-binding protein 7 essential to promote lipid signaling

Sortilin is a receptor for neuronal uptake of apolipoprotein E. Sortilin-dependent uptake of lipidated apoE promotes conversion of polyunsaturated fatty acids (PUFA) into neuromodulators that induce anti-inflammatory gene expression in the brain. This neuroprotective pathway works with apoE3 but is lost with apoE4, the main risk factor for Alzheimers disease (AD). Here, we elucidated steps in cellular handling of lipids through sortilin, and why they are disrupted by apoE4. Combining unbiased proteome screens with analyses in mouse models, we uncover interaction of sortilin with fatty acid-binding protein (FABP) 7, the intracellular carrier for PUFA in the brain. In the presence of apoE3, sortilin promotes functional expression of FABP7 and its ability to elicit lipid-dependent gene transcription. By contrast, apoE4 binding blocks sortilin sorting, causing catabolism of FABP7 and impairing lipid signaling. Reduced FABP7 levels in the brain of AD patients expressing apoE4 substantiate the relevance of these interactions for neuronal lipid homeostasis. Taken together, we document interaction of sortilin with mediators of extracellular and intracellular lipid transport that provides a mechanistic explanation for loss of a neuroprotective lipid metabolism in AD. SUMMARY STATEMENTLipids are central to brain health and defects in brain lipid homeostasis are causal to neurodegenerative processes in Alzheimers disease. Here, we uncovered how the neuronal lipoprotein receptor sortilin interacts with apoE and FABP7, the carriers for extra- and intracellular transport of lipids in the brain, respectively. We show that this interaction enables lipids to control gene transcription via nuclear receptors; and why this presumed neuroprotective lipid action is disturbed in humans who carry the {varepsilon}4 variant of apoE, the most important risk factor for sporadic Alzheimers disease.

cell biology↗

bioRxiv2020

Cdon Mutation and Fetal Alcohol Converge on Nodal Signaling in a Gene-Environment Interaction Model of Holoprosencephaly

Holoprosencephaly (HPE), a defect in midline patterning of the forebrain and midface, arises ~1 in 250 conceptions. It is associated with predisposing mutations in the Nodal and Hedgehog (HH) pathways, with penetrance and expressivity graded by genetic and environmental modifiers, via poorly understood mechanisms. CDON is a multifunctional co-receptor, including for the HH pathway. In mice, Cdon mutation synergizes with fetal alcohol exposure, producing HPE phenotypes closely resembling those seen in humans. We report here that, unexpectedly, Nodal, not HH, signaling is the point of synergistic interaction between Cdon mutation and fetal alcohol. Window-of-sensitivity, genetic, and in vitro findings are consistent with a model whereby brief exposure of Cdon mutant embryos to ethanol during gastrulation transiently and partially inhibits Nodal pathway activity, with consequent effects on downstream HH signaling during midline patterning. These results illuminate mechanisms of gene-environment interaction in a multifactorial model of a common birth defect.Competing Interest StatementThe authors have declared no competing interest.View Full Text

developmental biology↗

bioRxiv2020

Apolipoprotein E4 disrupts the neuroprotective action of sortilin in neuronal lipid metabolism and endocannabinoid signaling

INTRODUCTIONApoE is a carrier for brain lipids and the most important genetic risk factor for Alzheimers disease (AD). ApoE binds the receptor sortilin which mediates uptake of apoE-bound cargo into neurons. The significance of this uptake route for brain lipid homeostasis and AD risk seen with apoE4, but not apoE3, remains unresolved. METHODSCombining neurolipidomics in patient specimens with functional studies in mouse models, we interrogated apoE isoform-specific functions for sortilin in brain lipid metabolism and AD. RESULTSSortilin directs uptake and conversion of polyunsaturated fatty acids into endocannabinoids, lipid-based neurotransmitters that act through nuclear receptors to sustain neuroprotective gene expression in the brain. This sortilin function requires apoE3, but is disrupted by binding of apoE4, impairing endocannabinoid signaling and increasing amyloidogenic processing. DISCUSSIONWe uncovered the significance of neuronal apoE receptor sortilin in facilitating neuroprotective actions of brain lipids, and its relevance for AD risk seen with apoE4.

neuroscience↗