Dataset Information

Familial Alzheimer disease mutation in SORL1 impairs release of neurotrophic extracellular vesicles by microglia

ABSTRACT: Coding mutations in SORL1, the gene encoding sortilin-related receptor with A-type repeats (SORLA) are common in individuals suffering from Alzheimer’s disease (AD) of unknown etiology. These findings suggest SORL1 as a novel familial disease gene causative of AD. SORL1 mutations characterized so far have mainly been shown to impact folding and maturation of the receptor polypeptide. While these previous findings support the relevance of SORLA dysfunction for AD pathology, they provide little information about activity of this intracellular sorting receptor crucial for aging brain health. Here, we have characterized the N1358S variant of SORLA, carrying a mutation in a major ligand binding domain of the receptor. Using unbiased interactome studies, we show that N1358S impacts the ability of SORLA to interact with proteins involved in formation and release of extracellular vesicle (EVs) from cells. Consequently, expression of SORLAN1358S in iPSC-derived human microglia impairs their ability to produce trophic EVs that support maturation of neurons, a defect also seen in microglia lacking the receptor. Our findings document a unique role for SORLA in microglia to neuron crosstalk through EVs, and suggest loss of neurotrophic support in the brain of SORL1N1358S carriers.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Christian Sommer

LAB HEAD: Prof. Dr. Matthias Selbach

PROVIDER: PXD061828 | Pride | 2025-09-15

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	Statler_20160127_KM_HS_Ina_SORLA_IP_05.raw	Raw
	Statler_20160128_KM_HS_Ina_SORLA_IP_06.raw	Raw
	Statler_20160128_KM_HS_Ina_SORLA_IP_07.raw	Raw
	Statler_20160128_KM_HS_Ina_SORLA_IP_08.raw	Raw
	Statler_20160128_KM_HS_Ina_SORLA_IP_13.raw	Raw

Items per page:

1 - 5 of 8

Publications

Familial Alzheimer's disease mutation identifies novel role of SORLA in release of neurotrophic exosomes.

Juul-Madsen Kristian K Rudolph Ina-Maria IM Gomes Jemila P JP Meyer Katrina K Ovesen Peter L PL Gorniak-Walas Malgorzata M Kokoli Marianna M Telugu Narasimha S NS von Tangen Sivertsen Malthe M Febbraro Fabia F Sutherland Duncan S DS Palmfeldt Johan J Diecke Sebastian S Andersen Olav M OM Selbach Matthias M Willnow Thomas E TE

Alzheimer's & dementia : the journal of the Alzheimer's Association 20250901 9

<h4>Introduction</h4>Mutations in SORL1, encoding the sorting receptor Sortilin-related receptor with A-type repeats (SORLA), are found in individuals with Alzheimer's disease (AD). We studied SORLA<sup>N1358S</sup>, carrying a mutation in its ligand binding domain, to learn more about receptor functions relevant for human brain health.<h4>Methods</h4>We investigated consequences of SORLA<sup>N1358S</sup> expression in induced pluripotent stem cell (iPSC)-derived human neurons and microglia, usi ...[more]

PMID: 40928027

Similar Datasets

Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4

Project description:Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly population without a cure or early diagnostics currently available. Despite the demonstrated ability of extracellular vesicles (EVs) to spread tau and Aβ pathology in AD models and their potential utility as a diagnostic and treatment-monitoring tool, our knowledge of human brain EV subpopulations, their molecular composition and roles in disease progression is very limited. Genome-wide association studies linked multiple AD genetic risk factors to microglia-specific pathways suggesting a potential role of microglia-derived EVs in AD progression. Here we are presenting a method for isolation of microglial CD11b-positive small EVs from cryopreserved human brain tissue and multi-omics analysis of the EVs from the parietal cortex of 4 late-stage AD (Braak V-VI) and 3 age-matched normal/low pathology (NL) cases. We identified a total of 1000 proteins by quantitative proteomics, analyzed 594 individual lipid species by targeted lipidomics, and 105 miRNAs using a NanoString miRNA expression panel. We found significant reduction in abundance of homeostatic microglia markers, P2RY12 and TMEM119, and increased levels of disease associated microglia markers, FTH1 and TREM2, in microglial EVs from AD brain compared to NL cases. Protein tau abundance was also significantly higher in AD brain-derived microglial EVs. These changes were accompanied by upregulation of synaptic and neuron-specific proteins in the AD group. Levels of free-cholesterol were elevated in microglial EVs from AD brain. Lipidomic analysis also revealed a pro-inflammatory lipid profile, endolysosomal dysfunction and significant AD-associated decrease in levels of docosahexaenoic acid (DHA)-containing polyunsaturated lipids of different classes, suggesting a potential defect in acyl-chain remodeling. Several immune pathways and senescence were among the top pathways controlled by 4 miRNAs significantly upregulated in the AD group. Our data suggest that loss of the homeostatic microglia signature in late AD stages may accompany endolysosomal impairment and release of undigested neuronal and myelin debris, including tau, through extracellular vesicles. These data validate a method of isolation of small cell-type specific EVs from human brain tissue, suggests new potential EV-associated markers and disease-related pathways, and provides a framework for future large-scale multi-omics study.