bims-micgli 2025-11-09 papers

bims-micgli

Biomed News

on Microglia

Issue of 2025–11–09
thirteen papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer's disease.
Microglia alter sex-specific cerebellar myelination following placental hormone loss.
Gene module-trait network analysis uncovers cell type specific systems and genes relevant to Alzheimer's Disease.
Lymphoid gene expression supports neuroprotective microglia function.
Fatty acid-binding protein 4 drives microglia-mediated neuroinflammation through promoting S100A9 expression and lipid droplet accumulation after intracerebral hemorrhage.
Amyloid-β Seeds in Alzheimer's Disease: Research Challenges and Implications.
l-Fucose is a candidate monosaccharide neuromodulator and mitigates Alzheimer's synaptic deficits.
Sex- and cell type-specific effects of dexmedetomidine on ferroptosis in neurons and microglia following traumatic brain injury in juvenile mice.
Pathobiology of the autophagy-lysosomal pathway in the Huntington's disease brain.
DKK3-LRP1 complex and a chemical inhibitor regulate Aβ clearance in models of Alzheimer's disease.
Microglial Morphological Changes and Activation in Chronic Cerebral Hypoperfusion Are Suppressed by Lipid Peroxidation Inhibitor, Methyldopa.
Targeting lysosomal acidification to restore microglial homeostasis and mitigate memory decline during male brain ageing.
Transaldolase 1 impacts Parkinson's disease pathogenesis via metabolic reprogramming and autophagy-lysosomal pathway.

Nat Neurosci. 2025 Nov 06.

Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer's disease.

João Pedro Ferrari-Souza, Guilherme Povala, Nesrine Rahmouni, Bruna Bellaver, Pamela C L Ferreira, Marco Antônio De Bastiani, Douglas T Leffa, Firoza Z Lussier, Cristiano S Aguzzoli, Wagner S Brum, Giovanna Carello-Collar, Wyllians V Borelli, Joseph Therriault, Arthur C Macedo, Stijn Servaes, Jenna Stevenson, Ilaria Pola, Serge Gauthier, Diogo O Souza, Lucas Porcello Schilling, Mychael V Lourenco, Gallen Triana-Baltzer, Hartmuth C Kolb, Andréa L Benedet, Nicholas J Ashton, Dana L Tudorascu, Henrik Zetterberg, Kaj Blennow, Sterling C Johnson, Tharick A Pascoal, Pedro Rosa-Neto, Eduardo R Zimmer.

Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer's disease (AD). In this study, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in individuals across the AD spectrum. We examined 101 individuals using positron emission tomography radiotracers to assess Aβ deposition ([18F]AZD4694), tau aggregation ([18F]MK-6240) and microglial activation ([11C]PBR28), along with plasma biomarkers for astrocyte reactivity (GFAP) and tau phosphorylation (p-tau217). We further evaluated 251 individuals with cerebrospinal fluid levels of the microglial marker sTREM2. We found that Aβ pathology was associated with astrocyte reactivity across cortical brain regions only in the presence of microglial activation. The microglia-dependent effects of Aβ on astrocyte reactivity were further related to cognitive impairment through tau phosphorylation and aggregation. Our results suggest that microglial activation plays a key role in Aβ-related astrocyte reactivity, which, in turn, contributes to downstream pathological features of AD.

DOI: https://doi.org/10.1038/s41593-025-02103-0
Nat Commun. 2025 Nov 07. 16(1): 9846

Microglia alter sex-specific cerebellar myelination following placental hormone loss.

Jacquelyn Salzbank, Helene Lacaille, Jenah Gaby, Jiaqi J O'Reilly, Michael Kissner, Claire-Marie Vacher, Anna A Penn.

Placental dysfunction is linked to neurodevelopmental disorders, with males showing greater vulnerability to perinatal inflammation-mediated brain injuries. Using our transgenic mouse model, Akr1c14cyp19aKO (plKO), we investigate how reduced placental allopregnanolone (ALLO), an anti-inflammatory neurosteroid, contributes to sex-specific brain injury. plKO mice display sex-divergent cerebellar myelination and male-specific autism-like behaviors. Here we show that placental ALLO insufficiency triggers sex-divergent neuroinflammatory responses and microglial dysfunction. Sex-divergent differential expression of inflammatory genes and distinct inflammatory cytokine/chemokine patterns are seen in the placenta and the brain. Prostaglandin E2 (PGE2)-EP4 signaling is identified as a key regulator and, consistent with male plKO cerebellar hypermyelination, male microglial myelin phagocytosis is impaired by SIRPα-CD47 signaling changes. Postnatal manipulation of these critical pathways can normalize cerebellar myelin content and rescue abnormal behavior in male plKO mice. Sex-divergent microglial dysfunction and prostaglandin signaling drive male-biased neurodevelopmental impairments in our model, suggesting new therapeutic targets to improve brain development following placental dysfunction.

DOI: https://doi.org/10.1038/s41467-025-64814-z
Acta Neuropathol Commun. 2025 Nov 04. 13(1): 222

Gene module-trait network analysis uncovers cell type specific systems and genes relevant to Alzheimer's Disease.

Katia de Paiva Lopes, Ricardo A Vialle, Gilad Green, Masashi Fujita, Chris Gaiteri, Vilas Menon, Julie A Schneider, Yanling Wang, Philip L De Jager, Naomi Habib, Shinya Tasaki, David A Bennett.

  Alzheimer's Disease (AD) is marked by the accumulation of pathology, neuronal loss, and gliosis and frequently accompanied by decline in cognition. Understanding brain cell interactions is key to identifying new therapeutic targets to slow its progression. Here, we used systems biology methods to analyze single-nucleus RNA sequencing (snRNASeq) data generated from dorsolateral prefrontal cortex (DLPFC) tissues of 424 participants in the Religious Orders Study or the Rush Memory and Aging Project (ROSMAP). We identified modules of co-regulated genes in seven major cell types and assigned them to coherent cellular processes. We showed that coexpression structure was conserved in the majority of modules across cell types, but we also found distinct communities with altered connectivity, especially when compared to bulk RNASeq, suggesting cell-specific gene co-regulation. These coexpression modules can also capture signatures of cell subpopulations and be influenced by cell proportions. Finally, we performed associations of modules with AD traits such as amyloid-β deposition, tangle density, and cognitive decline, and showed replications in an independent single-nucleus dataset. Using a Bayesian network framework, we modeled the direction of relationships between the modules and AD progression. We highlight one key module, the astrocytic module 19 (ast_M19), associated with cognitive decline through a subpopulation of stress-response cells. Our work provides cell-specific molecular networks modeling the molecular events leading to AD.

Keywords:  Alzheimer’s disease.; Cell-type specific; Human brain; Networks; Single-nucleus RNASeq; Systems biology

DOI:  https://doi.org/10.1186/s40478-025-02143-4
Nature. 2025 Nov 05.

Lymphoid gene expression supports neuroprotective microglia function.

Pinar Ayata, Jessica M Crowley, Matthew F Challman, Vinaya Sahasrabuddhe, Maud Gratuze, Sebastian Werneburg, Diogo Ribeiro, Emma C Hays, Violeta Durán-Laforet, Travis E Faust, Philip Hwang, Francisco Mendes Lopes, Chrysa Nikopoulou, Sarah Buchholz, Robert E Murphy, Taoyu Mei, Anna A Pimenova, Carmen Romero-Molina, Francesca Garretti, Tulsi A Patel, Claudia De Sanctis, Angie V Ramirez Jimenez, Megan Crow, Felix D Weiss, Jason D Ulrich, Edoardo Marcora, John W Murray, Felix Meissner, Andreas Beyer, Dan Hasson, John F Crary, Dorothy P Schafer, David M Holtzman, Alison M Goate, Alexander Tarakhovsky, Anne Schaefer.

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)1. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic2. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation3,4. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1low microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1low CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.

DOI: https://doi.org/10.1038/s41586-025-09662-z
J Neuroinflammation. 2025 Nov 07. 22(1): 263

Fatty acid-binding protein 4 drives microglia-mediated neuroinflammation through promoting S100A9 expression and lipid droplet accumulation after intracerebral hemorrhage.

Jiaqing He, Zijuan Qin, Haixiao Liu, Yaning Cai, Hao Wu, Tinghao Wang, Qing Hu, Yanni Xu, Pan Yang, Xun Wu, Yan Qu, Wei Guo.

   BACKGROUND: As primary immune sentinels of the central nervous system (CNS), microglia respond rapidly to acute brain injury and engage in dynamic crosstalk with infiltrating peripheral immune cells. This interplay critically shapes the neuroinflammatory microenvironment-a key determinant of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). Fatty acid-binding protein 4 (FABP4), an adipokine associated with metabolic disorders, is recognized as a pivotal modulator of inflammatory responses; however, its role in ICH-induced SBI remains undefined.
OBJECTIVES: To investigate the pathogenic functions of FABP4 in microglia after ICH, elucidate its molecular mechanisms, and develop targeted therapeutic strategies.
METHODS: Blood and brain tissue samples from ICH patients were analyzed to evaluate the relationships between FABP4 expression and prognosis. Behavioral tests, Nissl staining, and Golgi-Cox staining were used to quantify neuronal damage. Immunofluorescence and flow cytometry were used to assess microglial activation and immune cell infiltration. Transcriptomic, proteomic, co-immunoprecipitation, western blotting, and ChIP‒qPCR analyses were used to examine the FABP4 regulatory network. Brain-targeted nanoparticles were engineered to deliver FABP4-specific siRNA.
RESULTS: Clinical analyses revealed microglia-specific FABP4 upregulation in ICH patients, correlating with poor neurological outcomes. Microglial Fabp4 knockout in mice attenuated neuronal loss, ameliorated cerebral edema, and enhanced functional recovery after ICH. Mechanistically, FABP4 promoted lipid droplet accumulation and inhibited the ubiquitin-proteasome-mediated degradation of S100A9 in microglia, synergistically amplifying neuroinflammation. Moreover, the activity of FABP4 in microglia facilitated neutrophil transendothelial migration into the brain parenchyma, exacerbating injury via the release of neutrophil extracellular traps (NETs). Finally, pharmacological FABP4 inhibition using brain-targeted nanoparticles conferred significant neuroprotective effects in ICH models.
CONCLUSION: This study establishes that FABP4 acts as a novel orchestrator of post-ICH neuroinflammation through dual enzymatic and nonenzymatic pathways. We also demonstrate a targeted nanotherapeutic strategy to suppress FABP4 and improve neurological outcomes.

Keywords:  FABP4; Intracerebral hemorrhage; Lipid droplet; Microglia; Neutrophil; S100A9

DOI:  https://doi.org/10.1186/s12974-025-03573-6
J Neurochem. 2025 Nov;169(11): e70267

Amyloid-β Seeds in Alzheimer's Disease: Research Challenges and Implications.

Natalie Beschorner, Ying Xu, Mathias Jucker, Alejandro Ruiz-Riquelme.

  The amyloid cascade hypothesis, proposed over 30 years ago, places amyloid-β (Aβ) at the center of Alzheimer's disease (AD) pathogenesis. Though controversial, recent clinical successes with Aβ-targeting therapies have reinforced its importance. However, these treatments have shown only modest clinical benefits in line with a two-stage AD progression: an early phase driven by Aβ-seed and a later phase that progresses at least partly independently of Aβ. Evidence of Aβ seed transmission in humans raises both therapeutic potential and biosafety concerns. This review explores current understanding of Aβ seeds, including challenges in studying such seeds, model systems to study Aβ seeds, and biosafety issues when working with Aβ seeds.

Keywords:  Alzheimer's disease; amyloid beta; neurodegeneration; prion; seeding

DOI:  https://doi.org/10.1111/jnc.70267
Sci Adv. 2025 Nov 07. 11(45): eadt4123

l-Fucose is a candidate monosaccharide neuromodulator and mitigates Alzheimer's synaptic deficits.

Jacopo Di Lucente, Jennyfer Tena, Yuanyuan Bai, Catelynn C Shafer, Ulises Ruiz Mendiola, Elizabeth K Neumann, Xi Chen, Carlito B Lebrilla, Izumi Maezawa, Lee-Way Jin.

Fucosylation, a major glycan modification, has been shown to influence neuronal and microglial mechanisms, but whether unconjugated free l-fucose can affect brain function is unknown. l-Fucose can be transported into cells and metabolized by fucokinase (FCSK) via the poorly understood salvage pathway. Using mouse hippocampal slices, we showed that l-fucose enhanced excitatory neurotransmission and long-term potentiation (LTP) through regulation of presynaptic release. Such effects required l-fucose be metabolized through the FCSK-driven salvage pathway, suggesting a metabolic-signaling mechanism. Human Alzheimer's disease (AD) and 5xFAD mouse brains showed signs of fucose hypometabolism with impaired l-fucose signaling. Such abnormalities were corrected by exogenous l-fucose, exemplified by rectification of LTP deficits in 5xFAD hippocampus. A dietary l-fucose supplement, which increased cerebral free l-fucose levels and up-regulated FCSK to drive the salvage pathway, mitigated synaptic and behavioral deficits of 5xFAD mice. Our data suggest an unrecognized neuromodulatory function of free l-fucose and reveals its therapeutic potential for AD.

DOI: https://doi.org/10.1126/sciadv.adt4123
Mol Neurobiol. 2025 Nov 06. 63(1): 4

Sex- and cell type-specific effects of dexmedetomidine on ferroptosis in neurons and microglia following traumatic brain injury in juvenile mice.

Jie Fan, Stefanie Tasevski, Yara Mashal, Tia Atoui, Zahrah Naseer, Zhi Zhang.

  Ferroptosis plays a key role in neuronal death and functional outcomes following traumatic brain injury (TBI). While TBI affects diverse cell types in injured brain regions, the sex- and cell type-specific responses to ferroptosis during the acute phase in the immature brain remain poorly understood. Dexmedetomidine (DEX), a selective alpha-2 adrenergic receptor agonist, has been shown to reduce inflammation and improve survival outcomes in TBI patients, but its sex- and cell type-specific effects on ferroptosis are unclear. This study investigated whether TBI induces sex- and cell type-specific ferroptotic responses and examined the effects of DEX during the acute post-injury phase in a juvenile mouse model. By concurrently isolating neurons and microglia from the same animals, we demonstrate that TBI prompts distinct sex- and cell type-specific ferroptosis responses, including differential regulation of genes involved in iron and lipid metabolism, oxidative stress, and proinflammatory pathways in neurons and microglia. DEX treatment significantly improved behavioral outcomes and reduced iron overload, lipid peroxidation, and neuroinflammation, thereby decreasing ferroptosis in both neurons and microglia. However, its effects were less prominent in neurons from female mice. Further analysis indicated that these sex- and cell type-specific responses to DEX may be partially due to differences in alpha-2 adrenergic receptor expression in neurons and microglia following TBI. Overall, our findings offer new insights into the mechanisms underlying sex- and cell type-specific responses to ferroptosis and DEX treatment, highlighting the broader implications for lipid metabolism, oxidative stress, and inflammation in the immature brain during the acute phase after TBI.

Keywords:  Ferroptosis; Inflammation; Microglia; Neuron; Oxidative stress; TBI

DOI:  https://doi.org/10.1007/s12035-025-05281-x
Acta Neuropathol Commun. 2025 Nov 07. 13(1): 228

Pathobiology of the autophagy-lysosomal pathway in the Huntington's disease brain.

Martin J Berg, Veeranna, Corrinne M Rosa, Asok Kumar, Panaiyur S Mohan, Philip Stavrides, Sandipkumar Darji, Deanna M Marchionini, Dun-Sheng Yang, Ralph A Nixon.

   BACKGROUND: Accumulated levels of mutant huntingtin protein (mHTT) and its fragments are considered contributors to the pathogenesis of Huntington's disease (HD). Stimulating autophagy may enhance clearance of mHTT and its aggregates which has been considered as a possible therapeutic strategy. However, the role and competence of the autophagy-lysosomal pathway (ALP) during HD progression in the human disease remains largely unknown.
METHODS: Here, we used multiplex confocal and ultrastructural immunocytochemical analyses of ALP functional markers in relation to mHTT aggresome pathology in striatum and the less affected cortex or cerebellum of HD brains staged from Grade HD2 to HD4 by Vonsattel neuropathological criteria compared to controls.
RESULTS: Immunolabeling revealed the localization of HTT/mHTT in ALP vesicular compartments labeled by autophagy-related adaptor proteins sequestosome 1 (p62/SQSTM1) and ubiquitin, and cathepsin D (CTSD) as well as HTT-positive inclusions. Although comparatively normal at HD2, neurons at later HD stages exhibited progressive enlargement and clustering of CTSD-immunoreactive autolysosomes/lysosomes and, ultrastructurally, autophagic vacuole/lipofuscin granules accumulated progressively, more prominently in striatum than cortex. These changes were accompanied by rises in levels of HTT/mHTT and p62/SQSTM1, particularly their fragments, in striatum but not in the cortex, and by increases of LAMP1 and LAMP2 RNA and LAMP1 protein. In addition, cargo-loaded autophagosomes and cathepsin-positive autolysosomes were readily observed, implying a lack of significant blockage in autophagosome formation and autophagosome-lysosome fusion.
CONCLUSIONS: The findings collectively suggest that upregulated lysosomal biogenesis and preserved proteolysis maintain autophagic clearance in early-stage HD, but the observed progressive HTT build-up and AL accumulation at advanced disease stages may signify a failure in autophagy substrate clearance. These findings support the prospect that ALP stimulation applied at early disease stages, when clearance machinery is fully competent, could lead to therapeutic benefits in HD patients.

Keywords:  Autophagy; Human brain; Huntington’s disease; Lysosome; Pathobiology

DOI:  https://doi.org/10.1186/s40478-025-02131-8
Sci Adv. 2025 Nov 07. 11(45): eadz2099

DKK3-LRP1 complex and a chemical inhibitor regulate Aβ clearance in models of Alzheimer's disease.

Ruihan Yang, Lin Wang, Yue Li, Jian Zhu, Juxian Wang, David Schlessinger, Jian Sima.

Impaired clearance of amyloid-β (Aβ) contributes to Alzheimer's disease (AD) pathogenesis, but its upstream modulators remain poorly defined. We report secreted Dickkopf (DKK) proteins-DKK1 through DKK4-as previously unrecognized ligands of low-density lipoprotein receptor-related protein 1 (LRP1), a principal Aβ clearance receptor. Analyses of cells derived from a patient with AD, postmortem tissue, and 5×FAD mice reveal that DKK1 and DKK3 are elevated in AD and reduce Aβ uptake and degradation in neurons and astrocytes. Mechanistically, DKKs inhibit Aβ clearance by competitively binding LRP1 and promoting its internalization. In 5×FAD mice, DKK3 overexpression worsens, while knockout improves, Aβ pathology and cognitive outcomes. A targeted high-throughput screen of ~3000 compounds identified SJ-300 as a potent and selective inhibitor of the DKK3-LRP1 interaction. SJ-300 restores Aβ clearance and rescues cognitive function and neuropathology in 5×FAD mice. These findings uncover DKK3-LRP1 axis as a contributor for Aβ metabolism and nominate SJ-300 as a promising therapeutic candidate for AD intervention.

DOI: https://doi.org/10.1126/sciadv.adz2099
J Neurochem. 2025 Nov;169(11): e70287

Microglial Morphological Changes and Activation in Chronic Cerebral Hypoperfusion Are Suppressed by Lipid Peroxidation Inhibitor, Methyldopa.

Ryo Hagimori, Masami Abe, Ryoya Ueno, Senri Ko, Ryo Yamasaki, Noriko Isobe, Mirinthorn Jutanom, Kazushi Morimoto, Ken-Ichi Yamada.

  Vascular dementia (VaD) is the second most common cognitive disease, and chronic cerebral hypoperfusion (CCH) is one of the causes of VaD. In CCH, neuroinflammation by immune cells in the brain is a key pathological feature in the development of VaD. However, it is unclear whether the cells contributing to disease pathogenesis during CCH are resident microglia (MG) or infiltrating monocyte-derived macrophages (MΦs) owing to blood-brain barrier disruption. Therefore, we applied bilateral common carotid artery stenosis (BCAS) to Ccr2RFP/+; Cx3cr1GFP/+ mice capable of distinguishing between MG and MΦs and investigated MG activation and potential MΦs infiltration during disease progression. We discovered that MΦs did not infiltrate the brain up to four weeks after BCAS. In contrast, MG exhibited significant activation, predominantly to the pro-inflammatory M1 phenotype. Additionally, methyldopa (MD), a compound we previously revealed to have lipid peroxidation (LPO) inhibitory property and which attenuated cognitive impairment in BCAS mice, reduced morphological changes and activation of MG during CCH. MD treatment decreased 4-HNE-modified proteins, indicating that LPO products contribute to neuroinflammation in CCH. These findings suggest that MG are activated prior to cognitive impairment by CCH and that LPO inhibitor can suppress MG activation, thereby attenuating pathological progression.

Keywords:  chronic cerebral hypoperfusion; lipid peroxidation; microglia; neuroinflammation

DOI:  https://doi.org/10.1111/jnc.70287
Brain Behav Immun. 2025 Nov 04. pii: S0889-1591(25)00412-X. [Epub ahead of print] 106170

Targeting lysosomal acidification to restore microglial homeostasis and mitigate memory decline during male brain ageing.

Lorenzo Barrella, María Pilar Ramírez-Ponce, Victoria Vázquez-Román, Marta San Millán-Huang, María Dolores Maldonado, Juan Antonio Flores-Cordero, Eva Alés.

  Lysosomal dysfunction lies at the nexus of inflammaging, microglial dystrophy and synaptic fragility, making it an attractive target for brain rejuvenation. Here we demonstrate that a five-month oral course of ketotifen, an approved H1-antihistamine and mast-cell stabiliser, re-acidifies lysosomes in aged C57BL/6J male mice, restoring the quinacrine signal of peripheral macrophages and SIM-A9 microglia. This proton rebound is coupled to broad anti-cytokine effects: ketotifen attenuates lipopolysaccharide-evoked release of TNF-α, IL-1β and IL-10 in vitro and ex vivo. In the brain, the drug restores a highly ramified, homeostatic microglial morphology throughout the cortex and hippocampus. Ketotifen robustly elevates cortical synaptophysin and PSD-95 above age-matched levels. Behaviourally, ketotifen enhances spatial learning and object-location memory without altering locomotor activity or anxiety-like behaviour. Collectively, these findings identify lysosomal re-acidification as the initiating trigger of a multifaceted rejuvenation cascade that dampens multi-cytokine signalling, restores microglial morphology and preserves synaptic integrity. Because ketotifen is inexpensive, brain-permeable and already licensed for human use, our work unveils an immediately actionable geroprotective strategy to forestall early cognitive decline.

Keywords:  Brain ageing; Geroprotection; Ketotifen; Lysosomal acidification; Microglia; Neuroinflammation; Spatial memory

DOI:  https://doi.org/10.1016/j.bbi.2025.106170
Acta Neuropathol Commun. 2025 Nov 04. 13(1): 223

Transaldolase 1 impacts Parkinson's disease pathogenesis via metabolic reprogramming and autophagy-lysosomal pathway.

Zixin Tan, Huimin Hu, Hao Chen, Yuwan Lin, Miaomiao Zhou, Wenlong Zhang, Pingyi Xu, Xiang Chen.

  Parkinson's disease (PD) progression involves dopaminergic neurodegeneration and pathological α-synuclein aggregation, processes linked to metabolic dysregulation and autophagy-lysosomal pathway (ALP) impairment. Transaldolase1 (TAL1) is a key enzyme of the pentose phosphate pathway. While elevated TAL1 protein levels have been observed in postmortem substantia nigra of PD patients, the enzyme's functional role in disease pathogenesis remains undefined. In this study, we explored the role of TAL1 in PD-related pathologies using MPTP-induced and AAV-A53T mouse models. We demonstrate that TAL1 upregulation is associated with dopaminergic neuron degeneration across both experimental models. TAL1 knockdown activated TFEB-mediated transcription of autophagy-lysosomal genes (Ctsb, Ctsd, Lamp1, Becn1, and Map1Lc3b). In addition, targeted metabolomics revealed that TAL1 knockdown modulates the energy pathways, especially in the TCA cycle, and glycolysis. The neuroprotective effects were mediated through AMPK/mTORC1 pathway activation, evidenced by increased AMP levels, p-AMPK/AMPK ratios, and downstream ALP enhancement. Importantly, TAL1 inhibition improved locomotor function in AAV-A53T mice and normalized stride length in footprint analysis. Pathological experiments confirmed reduced phospho-α-synuclein level and preserved the neuron loss in substantia nigra. Our findings highlight TAL1 as a regulator of autophagy-lysosomal function and energy metabolism in PD-related experimental models, where its inhibition restores the degradation of α-synuclein through coordinated activation of autophagy-lysosomal clearance and energetic reprogramming. These results suggest that targeting TAL1 may offer a potential therapeutic approach to mitigate PD-associated neuropathology.

Keywords:  Autophagy-lysosomal pathway; Metabolic reprogramming; Parkinson’s disease; Transaldolase1

DOI:  https://doi.org/10.1186/s40478-025-02133-6