Gender differences in Alzheimer's may be associated with TLR4-LYN expression in damage associated microglia and neuronal phagocytosis
Open accessAbstract
The role of Aβ plaques and neurofibrillary tangles in Alzheimer's disease (AD) pathogenesis have recently come into question due to failure of many pharmaceutical agents targeting these deposits and detection of these misfolded proteins in normal human brains. Therefore, we investigated correlations between microglial activation and toll like receptor 4 (TLR4) and Lck/Yes novel tyrosine (LYN) kinase signaling in an AD mouse model. In this study, we used 5–6‐month‐old 5XFAD and wild type (WT) male and female mice. Immunohistochemistry (IHC) and flow cytometry (FC) were performed on their brains. Cognitive performance was assessed with the Barnes‐Maze. IHC showed more Ab aggregation in microglia of female 5XFAD mice compared to their male counterparts. Increased co‐localization of microglial TLR4 and LYN was also observed in AD more than WT and females more than males. IHC also suggests microglial phagocytosis of neurons in AD mice, which is supported by FC data. Our FC data also support the involvement of disease associated microglia (DAMs) in this process based on cytokine secretion. Cognitive assessment by the Barnes maze showed 5XFAD females performed worse than males. In this study, we investigated the relationship between microglial TLR4 and LYN kinase in 5XFAD male and females. Our data reveals a correlation between microglial TLR4 and LYN co‐localization and AD pathogenesis, more in females than males. Targeting microglial TLR4 and Lyn in DAMs may offer new therapeutic opportunities in the treatment of AD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Microglial Fcgr1 is involved in Aβ clearance via Fc-receptor-Syk-mediated phagocytosis.
“Like Syk, microglial Fcgr1 is involved Aβ clearance via Fc-receptor-Syk-mediated phagocytosis53.”
From Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models (2026) · cites this paper as [53]
The Discussion addresses Aβ clearance and TLR4–LYN signaling, while the ‘Microglial phagocytosis of neurons in AD mice’ section examines neuronal material, not Aβ clearance. Neither passage identifies Fcgr1 or an Fc-receptor–Syk phagocytosis pathway; searches for those terms found no supporting passage in our copy. Page numbers were not available. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935 · cited 1× · see citing works
“In the brain of AD patients, activated microglia are present around senile plaques and are thought to be involved in disease pathogenesis (Hansen et al., 2018).”
BackgroundRelationship of microglia and astrocytes to amyloid deposits of Alzheimer disease
Itagaki, S., McGeer, P. L., Akiyama, H., Zhu, S., & Selkoe, D. (1989) · Journal of Neuroimmunology · doi:10.1016/0165-5728(89)90115-x · Cited by 940 · see citing works
TLR signaling tailors innate immune responses in human microglia and astrocytes
Jack, C. S., Arbour, N., Manusow, J., Montgrain, V., Blain, M., McCrea, E., Shapiro, A., & Antel, J. P. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.7.4320 · Cited by 734 · cited 1× · see citing works
“The association of glial TLR4 in neuro ‐ inflammation and clearance of protein aggregates in neuro-degenerative disorders had been shown previously (Balducci et al., 2017; Islam, Vrionis, et al., 2022; Jack et al., 2005).”
BackgroundEimer, W. A., & Vassar, R. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-2 · Cited by 425 · cited 1× · see citing works
“The accumulation of A β deposited on the neuronal surface and synaptic terminals cause severe neurotoxicity, which ultimately leads (Eimer & Vassar, 2013).”
BackgroundA CD36-initiated Signaling Cascade Mediates Inflammatory Effects of β-Amyloid
Moore, K. J., El Khoury, J., Medeiros, L. A., Terada, K., Geula, C., Luster, A. D., & Freeman, M. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208788200 · Cited by 327 · see citing works
Balducci, C., Frasca, A., Zotti, M., La Vitola, P., Mhillaj, E., Grigoli, E., Iacobellis, M., Grandi, F., Messa, M., Colombo, L., et al. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.10.012 · Cited by 164 · cited 1× · see citing works
“The association of glial TLR4 in neuro ‐ inflammation and clearance of protein aggregates in neuro-degenerative disorders had been shown previously (Balducci et al., 2017; Islam, Vrionis, et al., 2022; Jack et al., 2005).”
BackgroundActivation of the <scp>NLRP</scp>3 inflammasome in microglia: the role of ceramide
Scheiblich, H., Schlütter, A., Golenbock, D. T., Latz, E., Martinez‐Martinez, P., & Heneka, M. T. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14225 · Cited by 147 · see citing works
Flagged first, then by citations
Research works printed but not linked: 33
- Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, … Ikezu T (2015). Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci, 18(11), 1584- 1593. doi:10.1038/nn.4132 [PubMed: 26436904] · DOI · Paper page
- Bachiller S, Jimenez-Ferrer I, Paulus A, Yang Y, Swanberg M, Deierborg T, & Boza-Serrano A (2018). Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response. Front Cell Neurosci, 12, 488. doi:10.3389/fncel.2018.00488 [PubMed: 30618635] · DOI
- Bolos M, Perea JR, Terreros-Roncal J, Pallas-Bazarra N, Jurado-Arjona J, Avila J, & Llorens- Martin M (2018). Absence of microglial CX3CR1 impairs the synaptic integration of adult-born hippocampal granule neurons. Brain Behav Immun, 68, 76-89. doi:10.1016/j.bbi.2017.10.002 [PubMed: 29017970] · DOI
- Choi JS, Kim HY, Chung JW, Chun MH, Kim SY, Yoon SH, & Lee MY (2005). Activation of Src tyrosine kinase in microglia in the rat hippocampus following transient forebrain ischemia. Neurosci Lett, 380(1-2), 1-5. doi:10.1016/j.neulet.2005.01.015 [PubMed: 15854740] · DOI
- Combs CK, Karlo JC, Kao SC, & Landreth GE (2001). beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci, 21(4), 1179-1188. Retrieved from https://www.ncbi.nlm.nih.gov/ pubmed/11160388 [PubMed: 11160388]
- Dhawan G, & Combs CK (2012). Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer's disease. J Neuroinflammation, 9, 117. doi:10.1186/1742-2094-9-117 [PubMed: 22673542] · DOI
- Dhawan G, Floden AM, & Combs CK (2012). Amyloid-beta oligomers stimulate microglia through a tyrosine kinase dependent mechanism. Neurobiol Aging, 33(10), 2247-2261. doi:10.1016/ j.neurobiolaging.2011.10.027 [PubMed: 22133278] · DOI
- Garlanda C, & Mantovani A (2013). Ligands and receptors of the interleukin-1 family in immunity and disease. Front Immunol, 4, 396. doi:10.3389/fimmu.2013.00396 [PubMed: 24312101] · DOI
- M, Kou J, Lim JE, Yang J, & Fukuchi KI (2016). Microglial response to LPS increases in wild-type mice during aging but diminishes in an Alzheimer's mouse model: Implication of TLR4 signaling in disease progression. Biochem Biophys Res Commun, 479(2), 331-337. doi:10.1016/ j.bbrc.2016.09.073 [PubMed: 27641666] · DOI
- M, & El Khoury J (2015). beta-amyloid, microglia, and the inflammasome in Alzheimer's disease. Semin Immunopathol, 37(6), 607-611. doi:10.1007/s00281-015-0518-0 [PubMed: 26251237] · DOI · Paper page
- Gonzalez H, Contreras F, & Pacheco R (2015). Regulation of the Neurodegenerative Process Associated to Parkinson's Disease by CD4+ T-cells. J Neuroimmune Pharmacol, 10(4), 561-575. doi:10.1007/s11481-015-9618-9 [PubMed: 26018603] · DOI · Paper page
- Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, … Golenbock DT (2013). NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature, 493(7434), 674-678. doi:10.1038/nature11729 [PubMed: 23254930] · DOI · Paper page
- Hu Y, Fryatt GL, Ghorbani M, Obst J, Menassa DA, Martin-Estebane M, … Gomez-Nicola D (2021). Replicative senescence dictates the emergence of disease-associated microglia and contributes to Abeta pathology. Cell Rep, 35(10), 109228. doi:10.1016/j.celrep.2021.109228 [PubMed: 34107254] · DOI · Paper page
- R, Choudhary H, Rajan R, Vrionis F, & Hanafy KA (2022). An overview on microglial origin, distribution, and phenotype in Alzheimer's disease. J Cell Physiol. doi:10.1002/jcp.30829 · DOI
- Islam R, Vrionis F, & Hanafy KA (2022). Microglial TLR4 is Critical for Neuronal Injury and Cognitive Dysfunction in Subarachnoid Hemorrhage. Neurocrit Care. doi:10.1007/ s12028-022-01552-w · DOI
- Katsura H, Obata K, Mizushima T, Sakurai J, Kobayashi K, Yamanaka H, … Noguchi K (2006). Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury. J Neurosci, 26(34), 8680-8690. doi:10.1523/JNEUROSCI.1771-06.2006 [PubMed: 16928856] · DOI
- Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, … Amit I (2017). A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell, 169(7), 1276-1290 e1217. doi:10.1016/j.cell.2017.05.018 [PubMed: 28602351] · DOI · Paper page
- Kettenmann H, Hanisch UK, Noda M, & Verkhratsky A (2011). Physiology of microglia. Physiol Rev, 91(2), 461-553. doi:10.1152/physrev.00011.2010 [PubMed: 21527731] · DOI · Paper page
- Ling EA, & Wong WC (1993). The origin and nature of ramified and amoeboid microglia: a historical review and current concepts. Glia, 7(1), 9-18. doi:10.1002/glia.440070105 [PubMed: 8423067] · DOI
- Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, … Investigators, C.-. (2008). Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke, 39(11), 3015-3021. doi:10.1161/STROKEAHA.108.519942 [PubMed: 18688013] · DOI
- McGeer PL, Kawamata T, Walker DG, Akiyama H, Tooyama I, & McGeer EG (1993). Microglia in degenerative neurological disease. Glia, 7(1), 84-92. doi:10.1002/glia.440070114 [PubMed: 8423066] · DOI · Paper page
- Merlo S, Spampinato SF, & Sortino MA (2017). Estrogen and Alzheimer's disease: Still an attractive topic despite disappointment from early clinical results. Eur J Pharmacol, 817, 51-58. doi:10.1016/j.ejphar.2017.05.059 [PubMed: 28577965] · DOI
- Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG, Leung BP, … Becher B (2018). High- Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease. Immunity, 48(2), 380-395 e386. doi:10.1016/ j.immuni.2018.01.011 [PubMed: 29426702] · DOI · Paper page
- Paolicelli RC, & Gross CT (2011). Microglia in development: linking brain wiring to brain environment. Neuron Glia Biol, 7(1), 77-83. doi:10.1017/S1740925X12000105 [PubMed: 22857738] · DOI
- Portugal CC, Almeida TO, Socodato R, & Relvas JB (2021). Src family kinases (SFKs): critical regulators of microglial homeostatic functions and neurodegeneration in Parkinson's and Alzheimer's diseases. FEBS J. doi:10.1111/febs.16197 · DOI
- Salter MW, & Kalia LV (2004). Src kinases: a hub for NMDA receptor regulation. Nat Rev Neurosci, 5(4), 317-328. doi:10.1038/nrn1368 [PubMed: 15034556] · DOI
- Schallner N, Pandit R, LeBlanc R 3rd, Thomas AJ, Ogilvy CS, Zuckerbraun BS, … Hanafy KA (2015). Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1. J Clin Invest, 125(7), 2609-2625. doi:10.1172/JCI78443 [PubMed: 26011640] · DOI
- Selkoe DJ (1991). The molecular pathology of Alzheimer's disease. Neuron, 6(4), 487-498. doi:10.1016/0896-6273(91)90052-2 [PubMed: 1673054] · DOI · Paper page
- Socodato R, Portugal CC, Domith I, Oliveira NA, Coreixas VS, Loiola EC, … Relvas JB (2015). c-Src function is necessary and sufficient for triggering microglial cell activation. Glia, 63(3), 497-511. doi:10.1002/glia.22767 [PubMed: 25421817] · DOI
- Su F, Bai F, Zhou H, & Zhang Z (2016). Microglial toll-like receptors and Alzheimer's disease. Brain Behav Immun, 52, 187-198. doi:10.1016/j.bbi.2015.10.010 [PubMed: 26526648] · DOI
- Tsuda M, Tozaki-Saitoh H, Masuda T, Toyomitsu E, Tezuka T, Yamamoto T, & Inoue K (2008). Lyn tyrosine kinase is required for P2X(4) receptor upregulation and neuropathic pain after peripheral nerve injury. Glia, 56(1), 50-58. doi:10.1002/glia.20591 [PubMed: 17918263] · DOI
- Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, … Fassbender K (2007). Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol Biochem, 20(6), 947-956. doi:10.1159/000110455 [PubMed: 17982277] · DOI · Paper page
- Zhao Y, Wu X, Li X, Jiang LL, Gui X, Liu Y, … Xu H (2018). TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function. Neuron, 97(5), 1023-1031 e1027. doi:10.1016/ j.neuron.2018.01.031 [PubMed: 29518356] · DOI · Paper page
Cited by
Sorted by citations
Islam, R., Choudhary, H. H., Zhang, F., Mehta, H., Yoshida, J., Thomas, A. J., & Hanafy, K. (2025) · Scientific Reports · doi:10.1038/s41598-025-96456-y · Cited by 22 · see citing works
Self-citationKim, B., Tate, M. D., Karahan, H., Wijeratne, H. R. S., Sharify, A. D., Wang, S. S., Kim, J. R., Al-Amin, M. M., Hartigan, K., Chung, S., et al. (2026) · Neuron · doi:10.1016/j.neuron.2026.03.011 · Cited by 6 · see citing works
- Authors
- Islam, R., Rajan, R., Choudhary, H., Vrionis, F., & Hanafy, K. A.
- Affiliations
- Florida Atlantic University (US)
- Department of Neuroscience, Marcus Neuroscience Institute Boca Raton Medical Center Boca Raton Florida USA
- Corresponding author
- Hanafy, Khalid A.
- Venue
- Journal of Cellular Physiology
- Publisher
- Wiley
- Published
- 2022-11-21
- Volume
- 239
- Issue
- 6
- Pages
- e30916-e30916
- ISSN
- 0021-9541 (ISSN-L)
- 1097-4652
- PMC
- PMC10199960
- OpenAlex
- W4309496699
- Cited by
- 13
- References
- 7
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 2 · 2023: 2
- FWCI
- 0.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Cellular Physiology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, gender differences, disease-associated microglia, TLR4, Lyn kinase, microglial activation, amyloid-beta aggregation, 5xFAD mice, cognitive impairment, cytokine production, sex differences
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cognition, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Neurons, Phagocytosis, Sex Characteristics, Sex Factors, Signal Transduction, Cytokines, Microglia, src-Family Kinases, Toll-Like Receptor 4, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
