bims-micgli 2025-11-02 papers

bims-micgli

Biomed News

on Microglia

Issue of 2025–11–02
twelve papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Alpha-synuclein deposition patterns in Alzheimer's disease: association with cortical amyloid beta and variable tau load.
Roles of TREM2 in Alzheimer's disease.
Soluble CSF1R promotes microglial activation and amyloid clearance in alzheimer's disease.
Stage-specific roles of clonally expanded CD8+ T cells in regulating amyloid pathology in Alzheimer's disease models.
The Parkinson's disease-associated LRRK2-G2019S variant restricts serine metabolism, leading to microglial inflammation and dopaminergic neuron degeneration.
Astrocytes distress triggers brain pathology through induction of δ secretase in a murine model of Alzheimer's disease.
Microglial NLRC5 drives lysosomal dysfunction to disrupt autophagic flux and promote post-stroke neuroinflammation.
Immune subversion by Leishmania infantum parasites suppresses NLRP3-driven inflammatory responses in amyloid-β-activated microglia.
Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions.
Endolysosomal dysfunction impairs proteostasis and induces neurodegeneration in vivo.
Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia.
Integrative brain omics approach highlights sn-1 lysophosphatidylethanolamine in Alzheimer's dementia.

Acta Neuropathol. 2025 Oct 30. 150(1): 46

Alpha-synuclein deposition patterns in Alzheimer's disease: association with cortical amyloid beta and variable tau load.

Antonia Neubauer, Doris Weissenbrunner, Susanna Pekrun, Sigrun Roeber, Viktoria Ruf, Paul Feyen, Felix L Strübing, Jochen Herms.

  Alpha-synuclein (α-syn) deposits are common in around half of the Alzheimer's disease (AD) cases. While direct and indirect protein interactions are suggested, the relationships between different protein aggregates remain poorly understood. Here, we aimed to characterize α-syn, amyloid beta (Aβ), and tau load distributions of AD patients. Protein deposits were automatically quantified with random forest pixel classifiers in immunohistochemical stains of up to 28 brain regions in 72 brains with advanced AD neuropathological change. α-syn-negative cases were distinguished from amygdala predominant, brainstem predominant, and cortical α-syn-positive cases. Relationships with age, sex, and ApoE genotype were examined. α-syn co-pathology was detected in 60% of AD cases, more frequently, although not significantly, in women. Half of these positive cases presented α-syn deposits in the cortex, around one-third predominantly in the amygdala, and the remaining cases primarily in the brainstem. A high α-syn load in the amygdala was associated with an increased cortical Aβ load. The cortical tau load was increased in the amygdala-predominant α-syn group, but decreased in the brainstem-predominant and cortical α-syn cases in comparison with α-syn-negative cases. ApoE4 was associated with higher hippocampal α-syn and cortical Aβ deposition. Younger age at death was associated with a focally higher Aβ and tau load. AD cases with cortical α-syn deposition tended to have a younger age at death. Here, we show that next to age, sex, and ApoE genotype, the α-syn distribution in AD is related to different Aβ and tau loads. This may have therapeutic relevance for identifying patients who respond to Aβ immunotherapy related to tau burden and underpin the need to define α-syn pathology and distribution in early disease stages.

Keywords:  Alpha-synuclein; Alzheimer’s disease; Immunohistochemistry; Lewy body disease; Mixed pathology; Quantitative neuropathology

DOI:  https://doi.org/10.1007/s00401-025-02952-w
Transl Neurodegener. 2025 Oct 31. 14(1): 55

Roles of TREM2 in Alzheimer's disease.

Xiaoshan Qi, Kedong Zhu, Wei Ke, Junjie Wang, Shanping Mao, Guiqin Chen.

  Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene have been demonstrated to increase the risk of late-onset Alzheimer's disease (AD) and Nasu-Hakola disease. As a type I transmembrane receptor, TREM2 is predominantly expressed in microglia within the central nervous system. Extensive research over the past decade has consistently established the critical role of TREM2 in AD pathogenesis, encompassing its regulation of microglial inflammatory responses, amyloid-β deposition, and tau pathology. Notably, the soluble TREM2 fragment (sTREM2) is emerging as a promising candidate biomarker for clinical progression of AD, as evidenced by human studies. Despite these advances, the precise roles of membrane-bound TREM2 and sTREM2 in AD pathogenesis remain incompletely elucidated. Novel mouse models and technological innovations have enabled therapeutic approaches targeting TREM2 for neuroprotection. This review summarizes this progress and highlights areas for future research towards the development of TREM2-directed therapeutics.

Keywords:  Alzheimer’s disease; Amyloid; Microglia; Soluble TREM2; TREM2; Tau; Therapeutic prospects; Variants

DOI:  https://doi.org/10.1186/s40035-025-00515-3
J Neuroinflammation. 2025 Oct 28. 22(1): 245

Soluble CSF1R promotes microglial activation and amyloid clearance in alzheimer's disease.

Lianshuai Zhang, Kai Chen, Ruicheng Zeng, Guojun Bu, Xiao-Fen Chen.

   BACKGROUND: The colony-stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase essential for microglial development and homeostasis. While dysregulated CSF1R signaling has been implicated in Alzheimer's disease (AD), the biological function of its soluble ectodomain (sCSF1R)-generated by a disintegrin and metalloproteinase 17 (ADAM17)-mediated cleavage-remains poorly understood in neurodegeneration.
METHODS: We quantified sCSF1R levels in the brain and cerebrospinal fluid (CSF) of 5×FAD transgenic mice and wild-type controls using ELISA and immunoblotting, and reanalyzed publicly available CSF proteomic datasets from three independent, clinically characterized AD cohorts. Functional studies were performed in primary microglial cultures and through hippocampal delivery of recombinant sCSF1R into 5×FAD mice to evaluate its effects on microglial activity and amyloid pathology.
RESULTS: In this study, we identify sCSF1R as a previously unrecognized, functionally active modulator of microglial responses in AD. Analysis of three independent clinical cohorts revealed significantly elevated sCSF1R levels in the CSF of AD patients, a finding recapitulated in both the brain and CSF of 5×FAD transgenic mice. Importantly, sCSF1R concentrations showed positive correlations with core AD biomarkers-including total tau, phosphorylated tau, and β-amyloid 1-42 (Aβ42)-and with measures of cognitive performance, highlighting its clinical significance and suggesting that sCSF1R may serve as a marker of disease-associated microglial responses. Functionally, recombinant sCSF1R enhanced microglial survival, migration, proinflammatory signaling, and Aβ phagocytosis in vitro. In vivo, administration of sCSF1R promoted microglial clustering around amyloid plaques, reduced Aβ deposition, and attenuated plaque-associated neuritic dystrophy in 5×FAD mice. Finally, we found that soluble TREM2 (sTREM2)-a CSF biomarker and potent activator of microglia-stimulates ADAM17-dependent cleavage of membrane-bound CSF1R, thereby driving the generation of sCSF1R. Collectively, these findings establish sCSF1R as a novel regulator of microglial function in AD and reveal a regulatory axis linking sTREM2, ADAM17 activity, and CSF1R shedding with potential implications for disease modulation.
CONCLUSIONS: These findings identify sCSF1R as a novel component of the neuroimmune signaling network in AD and highlight its dual potential as a CSF biomarker of beneficial microglial activation and a candidate therapeutic modulator of neuroinflammation and amyloid pathology.

Keywords:  Alzheimer’s disease; Amyloid-β; CSF1R; Microglia

DOI:  https://doi.org/10.1186/s12974-025-03558-5
Nat Commun. 2025 Oct 27. 16(1): 9458

Stage-specific roles of clonally expanded CD8+ T cells in regulating amyloid pathology in Alzheimer's disease models.

Masaki Ohyagi, Minako Ito, Mana Iizuka-Koga, Setsuko Mise-Omata, Akihiko Yoshimura.

Clonally expanded CD8+ T cells may contribute to Alzheimer's disease (AD) pathology through interactions with brain-resident cells. However, the functional impact of AD-specific T cell receptor (TCR) clonotypes remains unclear. Here, we demonstrate that CD8+ T cells undergo clonal expansion in early-stage AD mouse models, AppNL-G-F and 5xFAD, and that their depletion reduces amyloid plaque accumulation. Expanded TCR-expressing CD8+ T cells preferentially infiltrate the brain, exacerbating plaque deposition. Moreover, brain-infiltrating CD8+ T cells impair microglial transition into disease-associated states, suppressing amyloid clearance via CCL5-CCR5 signaling. Pharmacological blockade of CCL5 attenuates amyloid deposition, whereas CCL5 administration aggravates pathology. Notably, T cell depletion at later disease stages exacerbates amyloid pathology, suggesting a temporal shift in their function. Early-stage CD8+ T cells exhibit cytotoxic and effector profiles, whereas late-stage cells acquire tissue-resident and exhausted phenotypes. This temporal switch-from pathogenic to protective roles-highlights the stage-specific contribution of CD8+ T cells to AD and their potential as therapeutic targets.

DOI: https://doi.org/10.1038/s41467-025-64503-x
J Neuroinflammation. 2025 Oct 27. 22(1): 244

The Parkinson's disease-associated LRRK2-G2019S variant restricts serine metabolism, leading to microglial inflammation and dopaminergic neuron degeneration.

Henry Kurniawan, Sarah L Nickels, Alise Zagare, Elisa Zuccoli, Isabel Rosety, Gemma Gomez-Giro, Enrico Glaab, Jens C Schwamborn.

  A growing body of evidence implicates inflammation as a key hallmark in the pathophysiology of Parkinson's disease (PD), with microglia playing a central role in mediating neuroinflammatory signaling in the brain. However, the molecular mechanisms linking microglial activation to dopaminergic neuron degeneration remain poorly understood. In this study, we investigated the contribution of the PD-associated LRRK2-G2019S mutation to microglial neurotoxicity using patient-derived induced pluripotent stem cell (iPSC) models. We found that LRRK2-G2019S mutant microglia exhibited elevated activation markers, enhanced phagocytic capacity, and increased secretion of pro-inflammatory cytokines such as TNF-α. These changes were associated with metabolic dysregulation, including upregulated glycolysis and impaired serine biosynthesis. In 3D midbrain organoids, these overactivated microglia resulted in dopaminergic neuron degeneration. Notably, treating LRRK2-G2019S microglia with oxamic acid, a glycolysis inhibitor, attenuated microglial inflammation and reduced neuronal loss. Our findings underscore the link between metabolic targeting in microglia and dopaminergic neuronal loss in LRRK2-G2019S mutation, and highlight a potential strategy that warrants further preclinical evaluation.

Keywords:  Glycolysis; IPSC; LRRK2-G2019S; Metabolism; Microglia; Organoids; Parkinson’s disease; Serine

DOI:  https://doi.org/10.1186/s12974-025-03577-2
Nat Commun. 2025 Oct 31. 16(1): 9653

Astrocytes distress triggers brain pathology through induction of δ secretase in a murine model of Alzheimer's disease.

Vanessa Schmidt, Ewelina Ziemlinska, Tomasz Obrebski, Jemila P Gomes, Ewa Zurawska-Plaksej, Jaroslaw Cendrowski, Johan Palmfeldt, Barbara L Hempstead, Thomas E Willnow, Anna R Malik.

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

DOI: https://doi.org/10.1038/s41467-025-65536-y
J Neuroinflammation. 2025 Oct 31. 22(1): 253

Microglial NLRC5 drives lysosomal dysfunction to disrupt autophagic flux and promote post-stroke neuroinflammation.

Siyi Xu, Pinyi Liu, Junqiu Jia, Min Sun, Feiyu Ma, Rui Mao, Huiqin Li, Senlin Ji, Xinyu Bao, Shengnan Xia, Yun Xu, Xiang Cao.

   BACKGROUND: Ischemic stroke triggers excessive microglial activation and sustained neuroinflammation, driving secondary neuronal injury. Recent evidence suggests that dysfunction of the autophagy-lysosome system may be a crucial factor sustaining microglial pro-inflammatory responses, yet the underlying regulatory mechanisms remain unclear. NOD-like receptor family caspase recruitment domain-containing protein 5 (NLRC5) has been widely studied in various immune and inflammatory diseases and exhibits functional heterogeneity under different pathological conditions. However, the role of NLRC5 in modulating post-stroke neuroinflammation remains unclear.
METHODS: NLRC5 expression and localization was examined in a mouse transient middle cerebral artery occlusion (tMCAO) model and postmortem brain tissue from stroke patients. A microglia-specific Nlrc5 knockout (mCKO) mice line was generated to evaluate the effects of Nlrc5 deletion on neurological function, infarct volume, neuronal apoptosis, and inflammatory response after ischemic stroke. Proteomics, mass spectrometry, and molecular biology assays were conducted to elucidate the mechanisms.
RESULTS: NLRC5 expression was upregulated in the ischemic penumbra of mouse models and appeared higher in postmortem brain tissues from stroke patients, specifically in activated microglia. Strikingly, mCKO mice exhibited significantly improved neurological outcomes, reduced infarct volumes, and attenuated neuronal apoptosis post-stroke. In vitro studies demonstrated that NLRC5 induction by various stimuli, including oxygen-glucose deprivation/reperfusion (OGD/R), lipopolysaccharide (LPS), as well as neuronal debris and supernatant, promoted pro-inflammatory cytokine release and microglia-mediated neurotoxicity, whereas Nlrc5 deletion exerted protective effects. Mechanistically, NLRC5 did not influence autophagosome formation but profoundly disrupted autophagic flux by impairing lysosomal function. Proteomic and biochemical analyses revealed that NLRC5 binds interferon-stimulated gene 15 (ISG15) via its CARD domain, shielding ISG15 from autophagy-lysosomal degradation. Furthermore, NLRC5-induced lysosomal defects and inflammatory responses were abolished in the absence of Isg15.
CONCLUSION: NLRC5 promotes microglial inflammation and exacerbates post-stroke brain injury by stabilizing ISG15 and disrupting lysosomal function and autophagic flux. NLRC5-ISG15 axis is a therapeutic target for immune modulation in ischemic stroke.

Keywords:  Autophagy; Ischemic stroke; Lysosomal dysfunction; Microglia; NLRC5

DOI:  https://doi.org/10.1186/s12974-025-03585-2
J Neuroinflammation. 2025 Oct 29. 22(1): 252

Immune subversion by Leishmania infantum parasites suppresses NLRP3-driven inflammatory responses in amyloid-β-activated microglia.

Estefanía Calvo Alvarez, Chiara Sfogliarini, Francesca La Rosa, Marina Saresella, Maria Dolci, Elisabetta Vegeto, Donatella Taramelli, Nicoletta Basilico, Mario Clerici.

  Chronic activation of innate immune responses in the brain is increasingly recognized as a contributor to neurodegenerative diseases, including Alzheimer's disease (AD). AD remains a major global health challenge due to the inefficacy of current therapies to modify disease progression. In AD, hyperactivated microglia, the brain's resident macrophages, play a central role by responding to amyloid-beta peptides (Aβ) through activation of the NLRP3 inflammasome, a key innate immune sensor and a promising therapeutic target. Leishmania infantum, a protozoan parasite causing visceral leishmaniasis, is known to employ sophisticated mechanisms to subvert inflammatory responses in macrophages, including modulation of the NLRP3 inflammasome, thus representing a potential natural model for counteracting microglia-related inflammation. However, microglia-Leishmania interactions remain unexplored, particularly the parasite's ability to modulate microglial NLRP3 activation. Here, we demonstrate that L. infantum invades and persists in microglia without inducing cell activation, indicating an immunologically silent entry. Aβ-stimulated NLRP3 activation was suppressed by Leishmania infection, as evidenced by a significant reduction in key pro-inflammatory mediators, including IL-1β, IL-18, TNF-α, and neurotoxic nitric oxide. Mechanistically, L. infantum disrupted NLRP3 priming by interfering with NF-κB signaling and upregulating the negative regulator A20. Additionally, L. infantum limited ASC speck formation, caspase-1 activation and ROS production while preserving lysosomal integrity. These findings reveal, for the first time, an unrecognized inhibitory effect of L. infantum on the microglial NLRP3/NF-κB axis and provide mechanistic insights into the parasite's immune subversion in Aβ-activated microglia. Deciphering the molecular pathways exploited by L. infantum and the specific parasitic effectors involved could offer novel therapeutic targets and bioinspired strategies to mitigate microglial inflammatory responses in the context of AD.

Keywords:   Leishmania infantum ; Alzheimer’s disease; Amyloid-β; Immune subversion; Innate immunity; Microglia; Microglia-mediated inflammatory responses; NLRP3 inflammasome

DOI:  https://doi.org/10.1186/s12974-025-03574-5
Immunity. 2025 Oct 29. pii: S1074-7613(25)00433-9. [Epub ahead of print]

Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions.

Ruoqing Feng, Lena Spieth, Lu Liu, Stefan Berghoff, Jonas Franz, Qian Liu, Zhen Wang, Vini Tiwari, Simona Vitale, Simon Frerich, Sergi Florensa, Niklas Junker, Ludwig Huber, Marco Keller, Christoph Müller, Franz Bracher, Xiaoke Ge, Patrick C N Rensen, Gijs Kooij, Leon Hosang, Serhii Chornyi, Martin Dichgans, Ozgun Gokce, Gesine Saher, Christine Stadelmann, Martin Giera, Janos Groh, Mikael Simons.

  Compartmentalized inflammation is a key driver of multiple sclerosis (MS) progression, but the mechanisms sustaining its persistence remain unclear. A hallmark of this persistent and slowly evolving inflammatory process is chronic active MS lesions. We generated a high-resolution, single-cell molecular and spatial atlas of such lesions by combining single-nucleus RNA sequencing (snRNA-seq) with multiplexed error-robust fluorescence in situ hybridization (MERFISH). Within lesion rims, we identified CD8+ T cell niches associated with inflamed microglia displaying an interferon response and upregulated lipid metabolism. To investigate their function, we deleted ATP-binding cassette transporters A1 and G1 (ABCA1/G1) in the microglia of mice with experimental autoimmune encephalomyelitis (EAE), which increased the formation of lipid-storing phagocytes that amplified inflammation. Moreover, pharmacologically targeting sterol metabolism mitigated foam cell formation and inflammatory demyelination in EAE. Thus, our high-resolution map of immune niches in chronic active MS lesions identifies a role for lipid-storing, dysfunctional microglia in persistent neuroinflammation.

Keywords:  CD8+ T cells; CD8+ tissue-resident memory T cells; glia; lipids; microglia; multiple sclerosis; myelin; neuroinflammation; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.immuni.2025.10.003
iScience. 2025 Oct 17. 28(10): 113460

Endolysosomal dysfunction impairs proteostasis and induces neurodegeneration in vivo.

Wei Shao, Ellen A Albagli, Karen Jansen-West, Lillian M Daughrity, Jimei Tong, Anxhela Hysi, Peizhou Jiang, Tiffany W Todd, Emma Lee, Desiree Zanetti Alepuz, Yari Carlomagno, Mei Yue, Judith A Dunmore, Monica Castanedes-Casey, Paula Castellanos Otero, Aishe Kurti, Mercedes Prudencio, Casey N Cook, Dennis W Dickson, Tania F Gendron, Leonard Petrucelli, Yong-Jie Zhang.

  Transactive response (TAR) DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of the frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) spectrum. Dysfunction of the endolysosomal system, which plays a crucial role in protein trafficking and maintaining proteostasis, has been implicated in FTD-ALS pathogenesis. While the impact of endolysosomal dysfunction on TDP-43 pathology remains unclear, we demonstrated that disrupting the endolysosomal pathway by expressing the constitutively active endosomal protein, Rab5Q79L, induces TDP-43 aggregation in cultured cells. Here, we generated a mouse model expressing GFP-tagged Rab5Q79L, demonstrating that GFP-Rab5Q79L mice exhibit early motor deficits and endolysosomal dysfunction, including enlarged endosomes, abnormal lysosome morphology, and p62- or ubiquitin-positive inclusions. These mice also developed significant neuronal loss, neuroinflammation, phosphorylated TDP-43 (pTDP-43) inclusions, and nuclear envelope and nuclear pore structural defects reminiscent of FTD-ALS. Accordingly, GFP-Rab5Q79L mice will prove useful in expanding our understanding of endolysosomal dysfunction in proteostasis and pTDP-43 pathology.

Keywords:  developmental neuroscience; molecular neuroscience; technical aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.113460
Cell Death Dis. 2025 Oct 31. 16(1): 775

Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia.

Debjani Bhattacharya, Patricia da Silva-Buttkus, Karsten Nalbach, Lizhen Cheng, Lillian Garrett, Martin Irmler, Georg Kislinger, Georg Werner, Ramona Rodde, Christoph Lengger, Johannes Beckers, Annemarie Zimprich, Sabine M Hölter, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Benedikt Wefers, Wolfgang Wurst, Monika S Brill, Martina Schifferer, Stefan F Lichtenthaler, Christian Behrends.

Mutations in the gene encoding Tectonic β-propeller repeat-containing repeat protein 2 (TECPR2) cause hereditary sensory and autonomic neuropathy subtype 9 (HSAN9) which is a fatal neurodevelopmental and neurodegenerative disorder involving the sensory and peripheral nervous system. TECPR2 is ubiquitously expressed and linked to trafficking and sorting within the cell, however, its functional role remains poorly defined. Moreover, molecular insights into pathogenic mechanisms underlying HSAN9 are lacking. Here, we report a novel mouse model which harbors a HSAN9-associated nonsense mutation that causes loss of TECPR2 expression. Mice show altered gait, highly region-specific axonal dystrophy, and extensive local gliosis. The affected medulla area prominently features swollen axons filled with amorphous protein aggregates, glycogen granules, single and double membrane vesicles as well as aberrant organelles including ER and mitochondria whose proteome is distinctly altered. Despite the locally restricted pathology the neuronal demise is detectable in the cerebrospinal fluid and responded to by damage-associated microglia. However, their capacity to clear neuronal debris seems attenuated. Overall, neuronal and microglia phenotypes point to a dysfunctional endolysosomal system when TECPR2 is missing. This was confirmed in TECPR2 knockout cells and linked to TECPR2's interaction with the homotypic fusion and protein sorting (HOPS)-tethering complex. Collectively, we uncovered a role of TECPR2 in endolysosome maintenance which seems relevant for healthy neurons in a particular brain region.

DOI: https://doi.org/10.1038/s41419-025-08168-w
Nat Commun. 2025 Oct 31. 16(1): 9627

Integrative brain omics approach highlights sn-1 lysophosphatidylethanolamine in Alzheimer's dementia.

Chih-Yu Chen, Kristal Maner-Smith, Manoj Khadka, Jun Ahn, Xueyun L Gulbin, Anna A Ivanova, Eric B Dammer, Nicholas T Seyfried, David A Bennett, Ihab M Hajjar, Eric A Ortlund.

The biology of individual lipid species and their relevance in Alzheimer's disease (AD) remains incompletely understood. To explore the lipidomic biomarkers associated with cognition function and neuropathological changes in AD, we utilize non-targeted mass spectrometry on 316 post-mortem brains from participants in the Religious Orders Study (ROS) or Rush Memory and Aging Project (MAP) cohorts classified as control, asymptomatic AD (AAD), or symptomatic AD (SAD), and integrate the lipidomics data with untargeted proteomics from the same individuals. We find that lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) species are significantly lower in SAD than controls or AAD. Lipid-protein network analyses reveal that LPE/LPC modules are significantly associated with protein modules involved in MAPK/metabolism, post-synaptic density, and cell-ECM interaction pathways, and correlate with better antemortem cognition and reduced AD neuropathology. Particularly, LPE 22:6 [sn-1] is significantly decreased SAD and exerts a pronounced influence on protein changes relevant to neurotransmitter-driven post synaptic changes and plasticity compared to other lysophospholipids species. These findings suggest LPE 22:6 as a potential lipid signature and therapeutic target for AD.

DOI: https://doi.org/10.1038/s41467-025-64328-8