Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation

In the paper

“The inflammatory responses (especially neuroinflammation) accompany the entire progress of AD pathogenesis and are also linked to cognitive dysfunction [15].”

What the sources say

• Partly supported

  The ‘Clinical studies of immune dysregulation’ section reports a CNS inflammatory response early in AD and links some inflammatory markers to faster cognitive decline. The ‘Mechanistic insight from animal studies’ section describes chronic neuroinflammation contributing to disease progression and neuronal dysfunction. The source does not establish that inflammatory responses accompany the entire course of AD pathogenesis; it emphasizes stage-dependent patterns and mixed clinical associations. Page numbers were not available in our copy. (LLM, conf=0.85)

  cites [15] Bettcher BM, Tansey MG, Dorothee G, Heneka MT. Peripheral and central immune system crosstalk in Alzheimer disease—a research prospectus. Nat Rev Neurol. 2021;17:689–701. sourceExperimental — accuracy not yet measured

In the paper

“Even though it is encouraging that two of these drugs have recently received accelerated US Food and Drug Administration approval for AD treatment, their efficacy or long-term safety is controversial.”

What the sources say

• Partly supported

  In the paper’s main text (page unavailable), Kantarci reports accelerated FDA approval and disputed clinical benefit for aducanumab. It describes donanemab as the subject of a phase 2 trial, not as a second approved drug, and does not establish a controversy over long-term safety. (LLM, conf=0.87)

  cites [8] Kantarci K. 2021 marks a new era for Alzheimer’s therapeutics. Lancet Neurol. 2022;21:3–4. sourceExperimental — accuracy not yet measured
• Not checked yetcites [9] Mullard A. FDA approval for Biogen’s aducanumab sparks Alzheimer disease firestorm. Nat Rev Drug Discov. 2021;20:496–496.
• Partly supported

  The introduction (§10) says that one anti-amyloid antibody, aducanumab, had received accelerated FDA approval—not two. The conclusion (Table 3 continued) reports adverse events and calls for longer trials to determine lecanemab’s efficacy and safety, supporting uncertainty about longer-term outcomes, but it does not characterize the efficacy of two approved drugs as controversial. (LLM, conf=0.86)

  cites [10] van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9–21. sourceExperimental — accuracy not yet measured

In the paper

“The pathogenic tau can be released from diseased neurons, then uptake by previously unaffected normal neurons, inducing pathogenic tau production in normal neurons.”

What the sources say

• Supported

  The Transcellular tau transfer section (page unavailable) reports that tau seeds released from donor cells are taken up by recipient cells and induce aggregation of previously non-aggregated tau. It also reports neuron-to-neuron transfer of tau capable of seeding aggregation. The paper describes this mechanism chiefly through experimental studies; the claim says it can occur, not that it is established in human disease. (LLM, conf=0.88)

  cites [41] Mudher A, Colin M, Dujardin S, Medina M, Dewachter I, Naini SMA, Mandelkow EM, Mandelkow E, Buee L, Goedert M, Brion JP. What is the evidence that tau pathology spreads through prion-like propagation? Acta Neuropathol Commun. 2017;5:20. source
• Partly supported

  The Abstract (passages 5 and 7; no page given) reports that injected brain extract induced tau filament formation and spreading in transgenic mice expressing wild-type human tau. But the Abstract (passages 1 and 6) treats release from affected cells and entry into other cells as possible mechanisms requiring investigation, not as a demonstrated sequence. It also reports assembly of existing wild-type tau into filaments, rather than pathogenic tau production in normal neurons. (LLM, conf=0.88)

  cites [42] Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11:909-U325. sourceExperimental — accuracy not yet measured

In the paper

“HDAC6 knockdown attenuates reactive oxygen species (ROS) generation, NADPH oxidase activation, and neuroinflammation response in HIV-1 transactivator of transcription (Tat)-stimulated astrocytes [184].”

What the sources say

• Supported

  The Results sections report that HDAC6 knockdown reduced Tat-induced ROS generation and NADPH oxidase activity in CRT-MG cells and primary mouse astrocytes. The Discussion also states that knockdown suppressed subsequent expression of pro-inflammatory chemokines, supporting the claimed inflammatory response in astrocytes. No page numbers are provided in our copy. (LLM, conf=0.93)

  cites [184] Youn GS, Cho H, Kim D, Choi SY, Park J. Crosstalk between HDAC6 and Nox2-based NADPH oxidase mediates HIV-1 Tat-induced pro-inflammatory responses in astrocytes. Redox Biol. 2017;12:978–86. source

In the paper

“However, another study revealed that TREM2 knockout or its R47H variant decreases microgliosis around Aβ plaques and enhances the propagation of tau aggregates [70].”

What the sources say

• Supported

  The paper’s Abstract states that Trem2 knockout or the TREM2R47H variant reduces microgliosis around Aβ plaques and facilitates the seeding and spreading of neuritic-plaque tau aggregates. The study describes this effect in mice with Aβ plaques after tau seeding; the claim is consistent with that finding. (LLM, conf=0.94)

  cites [70] Leyns CEG, Gratuze M, Narasimhan S, Jain N, Koscal LJ, Jiang H, Manis M, Colonna M, Lee VMY, Ulrich JD, Holtzman DM. TREM2 function impedes tau seeding in neuritic plaques. Nat Neurosci. 2019;22:1217. source

In the paper

“As mentioned above, p38α MAPK is a key kinase involved in microglia-induced neuroinflammation leading to tau pathology [135, 137], and this kinase can also directly regulate tau phosphorylation [39].”

What the sources say

• Partly supported

  The Results report that reactive microglia induced tau hyperphosphorylation in mice and that blocking IL-1 signalling reduced p38 MAPK activation. The Introduction and Discussion also link microglial inflammation to tau pathology through the IL-1R–p38 MAPK pathway. The cited passages identify p38 MAPK, but not specifically the p38α isoform; the sentence cites a different source for the separate claim about direct regulation of tau phosphorylation. (LLM, conf=0.86)

  cites [135] Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, Lamb BT, Bhaskar K. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain. 2015;138:1738–55. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section, “p38 MAPK Promotes MAPT Phosphorylation Upon Exposure to Microglial Factors” (page unavailable), reports that microglial factors increased neuronal tau phosphorylation through a p38 MAPK-dependent pathway. The paper identifies p38 MAPK generally, not the p38α isoform specified in the cited clause. The separate statement about direct regulation of tau phosphorylation carries citation [39], so it is not judged as attributed to this source. (LLM, conf=0.86)

  cites [137] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of Tau Pathology by the Microglial Fractalkine Receptor. Neuron. 2010;68:19–31. sourceExperimental — accuracy not yet measured
• Supported

  The citation [39] is attached to the claim that p38α MAPK can directly regulate tau phosphorylation, not to the preceding claim about microglia-induced neuroinflammation. The Results report direct phosphorylation of recombinant tau by p38α in vitro, and the Discussion describes p38α-mediated multi-site tau phosphorylation in isolated protein and hippocampal neurons. Page numbers were not provided. (LLM, conf=0.94)

  cites [39] Stefanoska K, Gajwani M, Tan ARP, Ahel HI, Asih PR, Volkerling A, Poljak A, Ittner A. Alzheimer’s disease: ablating single master site abolishes tau hyperphosphorylation. Sci Adv. 2022. https://doi.org/10.1126/sciadv.abl8809. source

In the paper

“Mutations in the MAPT gene lead to FTDP-17 [22], providing evidence that tau dysfunction due to tau mutations induces neurodegeneration.”

What the sources say

• Not checked yetcites [22] Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, et al. Association of missense and 5 ’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393:702–5. source

In the paper

“In January 2023, FDA approved a new monoclonal antibody against Aβ called lecanemab for the treatment of early AD, also by its accelerated approval pathway.”

What the sources say

• Not checked yetcites [10] van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9–21. source

In the paper

“Furthermore, inhibition of endogenous tau improves behaviors and protects neurons from toxicity in APP/PS1 mice, a mouse model with AD-like Aβ pathology [31].”

What the sources say

• Not checked yetcites [31] Wegmann S, DeVos SL, Zeitler B, Marlen K, Bennett RE, Perez-Rando M, MacKenzie D, Yu Q, Commins C, Bannon RN, et al. Persistent repression of tau in the brain using engineered zinc finger protein transcription factors. Sci Adv. 2021. https://doi.org/10.1126/sciadv.abe1611. source

In the paper

“Moreover, inflammation, especially neuroinflammation, accompanies AD pathological processes and is also linked to cognitive deficits.”

What the sources say

• Not checked yetcites [15] Bettcher BM, Tansey MG, Dorothee G, Heneka MT. Peripheral and central immune system crosstalk in Alzheimer disease—a research prospectus. Nat Rev Neurol. 2021;17:689–701. source

In the paper

“The efficacy or long-term safety of these two drugs needs further validation.”

In the paper

“It is encouraging that in 2021, aducanumab, a humanized recombinant monoclonal antibody targeting Aβ, became the first disease-modifying therapy (DMT) drug for AD approved by an accelerated pathway of the US Food and Drug Administration (FDA).”

What the sources say

• Not checked yetcites [8] Kantarci K. 2021 marks a new era for Alzheimer’s therapeutics. Lancet Neurol. 2022;21:3–4. source
• Not checked yetcites [9] Mullard A. FDA approval for Biogen’s aducanumab sparks Alzheimer disease firestorm. Nat Rev Drug Discov. 2021;20:496–496.

In the paper

“Lecanemab reduced brain amyloid burden markedly in early AD and cognitive decline moderately than placebo at 18 months but was related to adverse events [10].”

What the sources say

• Not checked yetcites [10] van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9–21. source

In the paper

“Tau has received increasing attention as a potential therapeutic target, since evidence indicates that tau pathology is more associated with cognitive dysfunction.”

What the sources say

• Not checked yetcites [11] Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology. 1992;42:631–631. source
• Not checked yetcites [12] GomezIsla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, Parisi JE, Hyman BT. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol. 1997;41:17–24. source
• Not checked yetcites [13] Gong P, Chen YQ, Lin AH, Zhang HB, Zhang Y, Ye RD, Yu Y. p47(phox) deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD. Alzheimers Res Ther. 2020;12:18. source
• Not checked yetcites [14] Zhang HB, Lin AH, Gong P, Chen YQ, Ye RD, Qian F, Zhang Y, Yu Y. The chemokine-like receptor 1 deficiency improves cognitive deficits of AD mice and attenuates tau hyperphosphorylation via regulating tau seeding. J Neurosci. 2020;40:6991–7007. source

In the paper

“Furthermore, tau propagation-induced tau pathology is based on the spread of tau between neurons and the dissemination between neurons and glial cells [81, 82].”

What the sources say

• Not checked yetcites [81] Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li AM, Barker SJ, Foley AC, Thorpe JR, Serpell LC, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014;82:1271–88. source
• Not checked yetcites [82] Santello M, Toni N, Volterra A. Astrocyte function from information processing to cognition and cognitive impairment. Nat Neurosci. 2019;22:154–66. source

In the paper

“Exosomes carrying tau are taken up by local and remote cells and contribute to apoptosis and neuronal loss [79].”

What the sources say

• Not checked yetcites [79] Agosta F, Dalla Libera D, Spinelli EG, Finardi A, Canu E, Bergami A, Chiavetto LB, Baronio M, Comi G, Martino G, et al. Myeloid microvesicles in cerebrospinal fluid are associated with myelin damage and neuronal loss in mild cognitive impairment and alzheimer disease. Ann Neurol. 2014;76:813–25. source

In the paper

“In addition, the acetylation of tau is an early pathological feature of neurodegeneration. Acetylated tau inhibits its degradation, promotes pathological aggregation and propagation, and contributes to tauopathy [46–51].”

What the sources say

• Not checked yetcites [46] Min SW, Cho SH, Zhou YG, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010;67:953–66. source
• Not checked yetcites [47] Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP, Trojanowski JQ, Lee VMY. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun. 2011;2:9. source
• Not checked yetcites [48] Min SW, Chen X, Tracy TE, Li YQ, Zhou YG, Wang C, Shirakawa K, Minami SS, Defensor E, Mok SA, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015;21:1154. source
• Not checked yetcites [49] Irwin DJ, Cohen TJ, Grossman M, Arnold SE, McCarty-Wood E, Van Deerlin VM, Lee VMY, Trojanowski JQ. Acetylated tau neuropathology in sporadic and hereditary tauopathies. Am J Pathol. 2013;183:344–51. source
• Not checked yetcites [50] Caballero B, Bourdenx M, Luengo E, Diaz A, Sohn PD, Chen X, Wang C, Juste YR, Wegmann S, Patel B, et al. Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice. Nat Commun. 2021;12:2238. source
• Not checked yetcites [51] Shin M-K, Vazquez-Rosa E, Koh Y, Dhar M, Chaubey K, Cintron-Perez CJ, Barker S, Miller E, Franke K, Noterman MF, et al. Reducing acetylated tau is neuroprotective in brain injury. Cell. 2021;184:2715–32. source

In the paper

“Postmortem studies have shown that the spread of tau pathology in AD follows a predictable pattern, allowing neuropathological diagnosis of different AD stages defined by Braak staging (I–VI).”

What the sources say

• Not checked yetcites [57] Braak H, Braak E. Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging. 1997;18:S85–8. source

In the paper

“Sokolow et al. revealed that C-terminal truncated tau is abundant in the cortical pre-synaptic terminals, and tau cleavage promotes tau aggregation, secretion, and propagation in AD [66].”

What the sources say

• Not checked yetcites [66] Sokolow S, Henkins KM, Bilousova T, Gonzalez B, Vinters HV, Miller CA, Cornwell L, Poon WW, Gylys KH. Pre-synaptic C-terminal truncated tau is released from cortical synapses in Alzheimer’s disease. J Neurochem. 2015;133:368–79. source

In the paper

“Increased neuronal activity enhances the release of tau-containing exosomes [75] and exacerbates tau propagation and pathology [78].”

What the sources say

• Not checked yetcites [75] Wang Y, Balaji V, Kaniyappan S, Kruger L, Irsen S, Tepper K, Chandupatla R, Maetzler W, Schneider A, Mandelkow E, Mandelkow EM. The release and trans-synaptic transmission of Tau via exosomes. Mol Neurodegener. 2017;12:25. source
• Not checked yetcites [78] Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, Sanders DW, Cook C, Fu H, Boonen RA, et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 2016;19:1085–92. source

In the paper

“However, under pathological conditions, various highly increased post-translational modifications, such as hyperphosphorylation, destabilize the interaction of tau with microtubules [33] and enhance the capacity of tau to accumulate in the cytoplasm [34], leading to microtubule instability and transport dysfunction.”

What the sources say

• Not checked yetcites [33] Merrick SE, Trojanowski JQ, Lee VMY. Selective destruction of stable microtubules and axons by inhibitors of protein serine/threonine phosphatases in cultured human neurons (NT2N cells). J Neurosci. 1997;17:5726–37. source
• Not checked yetcites [34] Li CZ, Gotz J. Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discovery. 2017;16:863–83. source

In the paper

“there is a large amount of evidence indicating that the abnormally hyperphosphorylated or oligomeric tau can be secreted from neurons into the extracellular space, then be taken up by other normal neurons, and finally causes interneuronal transfer of tau pathology and spreading of tau toxicity across different brain regions [59–61]”

What the sources say

• Not checked yetcites [59] Alonso AD, Beharry C, Corbo CP, Cohen LS. Molecular mechanism of prion-like tau-induced neurodegeneration. Alzheimers Dement. 2016;12:1090–7. source
• Not checked yetcites [60] Takeda S, Wegmann S, Cho HS, Devos SL, Commins C, Roe AD, Nicholls SB, Carlson GA, Pitstick R, Nobuhara CK, et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain. Nat Commun. 2015;6:15. source
• Not checked yetcites [61] Dai CL, Hu W, Tung YC, Liu F, Gong CX, Iqbal K. Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated tau-induced pathology in 3 x Tg-AD mice. Alzheimers Res Ther. 2018;10:14. source

In the paper

“In addition, trans-synaptic tau propagation and aggregation can also be independent of the presence of endogenous soluble tau, but the absence of endogenous tau reduces its neurotoxicity [63].”

What the sources say

• Not checked yetcites [63] Wegmann S, Maury EA, Kirk MJ, Saqran L, Roe A, DeVos SL, Nicholls S, Fan Z, Takeda S, Cagsal-Getkin O, et al. Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity. Embo j. 2015;34:3028–41. source

In the paper

“Hyperphosphorylated tau leads to abnormal aggregation of tau protein, which loses its ability to stabilize microtubules, thereby impairing neuronal function [23].”

What the sources say

• Not checked yetcites [23] Hoglinger GU, Respondek G, Kovacs GG. New classification of tauopathies. Revue Neurologique. 2018;174:664–8. source

In the paper

“For example, reduced tau O-glycosylation could lead to increased phosphorylation, while the enhancement of O-glycosylation reduces the extent of tau phosphorylation [43–45].”

What the sources say

• Not checked yetcites [43] Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci USA. 2004;101:10804–9. source
• Not checked yetcites [44] Brunden KR, Trojanowski JQ, Lee VMY. Advances in tau-focused drug discovery for Alzheimer’s disease and related tauopathies. Nat Rev Drug Discovery. 2009;8:783–93. source
• Not checked yetcites [45] Wang JZ, Grundke-Iqbal I, Iqbal K. Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer’s disease. Nat Med. 1996;2:871–5. source

In the paper

“Glial cells such as microglia and astrocytes perform normal immune functions in CNS and also play a vital role in the spreading of pathological tau [80, 83].”

What the sources say

• Not checked yetcites [80] Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kugler S, Ikezu T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18:1584–93. source
• Not checked yetcites [83] Pearce MMP, Spartz EJ, Hong W, Luo L, Kopito RR. Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain. Nat Commun. 2015;6:6768. source

In the paper

“Evidence suggests that the pathological activation of glial cells and the release of inflammatory factors involved in neuroinflammation can exacerbate tau pathology via direct or indirect pathways, leading to neuronal damage and cognitive impairment, ultimately aggravating AD pathology [113, 114].”

What the sources say

• Not checked yetcites [113] Kitazawa M, Cheng D, Tsukamoto MR, Koike MA, Wes PD, Vasilevko V, Cribbs DH, LaFerla FM. Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer’s disease model. J Immunol. 2011;187:6539–49. source
• Not checked yetcites [114] Leyns CEG, Holtzman DM. Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener. 2017;12:50. source

In the paper

“Furthermore, since the immune response exists throughout the pathological progress of AD [104, 105], suggesting that it may also participate in and aggravate the disease development.”

What the sources say

• Not checked yetcites [104] Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405. source
• Not checked yetcites [105] Blasko I, Grubeck-Loebenstein B. Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer’s disease. Drugs Aging. 2003;20:101–13. source

In the paper

“In contrast, in tau-P301S transgenic mice, TREM2 deletion attenuates neuroinflammation and protects against neurodegeneration at a late stage without altering tau phosphorylation and aggregation [127].”

What the sources say

• Not checked yetcites [127] Leyns CEG, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina Serrano J, Robinson GO, Anderson E, Colonna M, Holtzman DM. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A. 2017;114:11524–9. source

In the paper

“Although the link between neuroinflammation and AD was discovered decades ago [102], it remains unclear whether it is a cause or a consequence of the disease.”

What the sources say

• Not checked yetcites [102] McGeer PL, Rogers J, McGeer EG. Inflammation, antiinflammatory agents, and Alzheimer’s disease: the last 22 years. J Alzheimers Dis. 2016;54:853–7. source

In the paper

“Interestingly, the upregulation of such proinflammatory cytokine has been observed even before signs of increased Aβ and hyperphosphorylated tau in CSF of mild cognitive impairment (MCI) patients [101], suggesting that the inflammatory processes had occurred in the early stages of AD.”

What the sources say

• Not checked yetcites [101] Schuitemaker A, Dik MG, Veerhuis R, Scheltens P, Schoonenboom NSM, Hack CE, Blankenstein MA, Jonker C. Inflammatory markers in AD and MCI patients with different biomarker profiles. Neurobiol Aging. 2009;30:1885–9. source

In the paper

“This chronic neuroinflammation is caused by persistent activation of glial cells and excessive release of cytotoxic molecules, which adversely affects brain function and is a major cofactor in the pathogenesis of many neurodegenerative disorders, including AD [84].”

What the sources say

• Not checked yetcites [84] Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (NY). 2018;4:575–90. source

In the paper

“Deletion of CX3CR1 or depression of the CX3CL1/CX3CR1 axis reduces Aβ deposition [130–132] but exacerbates tau pathology, such as increased phosphorylation and aggregation of tau, and this is associated with worsened behavioral and cognitive impairments [132–137] (Fig. 1).”

What the sources say

• Not checked yetcites [130] Liu Z, Condello C, Schain A, Harb R, Grutzendler J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis. J Neurosci. 2010;30:17091–101. source
• Not checked yetcites [131] Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, Lamb BT. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol. 2010;177:2549–62. source
• Not checked yetcites [132] Puntambekar SS, Moutinho M, Lin PBC, Jadhav V, Tumbleson-Brink D, Balaji A, Benito MA, Xu GX, Oblak A, Lasagna-Reeves CA, et al. CX3CR1 deficiency aggravates amyloid driven neuronal pathology and cognitive decline in Alzheimer’s disease. Mol Neurodegener. 2022;17:21. source
• Not checked yetcites [133] Lee S, Xu G, Jay TR, Bhatta S, Kim KW, Jung S, Landreth GE, Ransohoff RM, Lamb BT. Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway. J Neurosci. 2014;34:12538–46. source
• Not checked yetcites [134] Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, Haass C, LaFerla FM, Kretzschmar H, Herms J. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci. 2010;13:411–3. source
• Not checked yetcites [135] Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, Lamb BT, Bhaskar K. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain. 2015;138:1738–55. source
• Not checked yetcites [136] Fan Q, He W, Gayen M, Benoit MR, Luo X, Hu X, Yan R. Activated CX3CL1/Smad2 signals prevent neuronal loss and alzheimer’s tau pathology-mediated cognitive dysfunction. J Neurosci. 2020;40:1133–44. source
• Not checked yetcites [137] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of Tau Pathology by the Microglial Fractalkine Receptor. Neuron. 2010;68:19–31. source

In the paper

“These findings reveal a pivotal role in the cell-to-cell spreading of abnormal tau in neurotoxicity and provide potential therapeutic strategies for tau-targeted immunotherapies in AD and other tauopathies.”

In the paper

“In the CSF of AD patients, the R47H (rs75932628) variant of TREM2 or soluble TREM2 has been found to correlate with total or phosphorylated tau (Thr181), respectively, but not with Aβ42 [124, 125].”

What the sources say

• Not checked yetcites [124] Lill CM, Rengmark A, Pihlstrom L, Fogh I, Shatunov A, Sleiman PM, Wang LS, Liu T, Lassen CF, Meissner E, et al. The role of TREM2 R47H as a risk factor for Alzheimer’s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson’s disease. Alzheimers Dement. 2015;11:1407–16. source
• Not checked yetcites [125] Piccio L, Deming Y, Del-Aguila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016;131:925–33. source

In the paper

“Astrocytes are the most abundant glial cells in the brain and have a variety of complex and essential functions in CNS, including maintenance of brain homeostasis, synaptic transmission, and information processing through neural circuits [94].”

What the sources say

• Not checked yetcites [94] Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35. source

In the paper

“TREM2, a pivotal risk factor for LOAD [119, 120], is associated with tau pathology.”

What the sources say

• Not checked yetcites [119] Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med. 2013;368:107–16. source
• Not checked yetcites [120] Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med. 2013;368:117–27. source

In the paper

“Microglia are the resident immune cells of the brain and play a pivotal role in the immune defense of CNS.”

What the sources say

• Not checked yetcites [86] Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–8. source

In the paper

“Astrocytes become activated in AD and exhibit certain immune functions.”

What the sources say

• Not checked yetcites [95] Carrero I, Gonzalo MR, Martin B, Sanz-Anquela JM, Arevalo-Serrano J, Gonzalo-Ruiz A. Oligomers of beta-amyloid protein (A beta 1–42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1beta, tumour necrosis factor-alpha, and a nuclear factor kappa-B mechanism in the rat brain. Exp Neurol. 2012;236:215–27. source
• Not checked yetcites [96] Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W. Astrocytes are important mediators of Abeta-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis. 2011;2: e167. source

In the paper

“Our and other studies found that systemic administration of lipopolysaccharide (LPS, inducer of inflammation) leads to microglial activation in the mouse brain, which results in tau hyperphosphorylation at specific sites [117, 118].”

What the sources say

• Not checked yetcites [117] Liu J, Wang D, Li SQ, Yu Y, Ye RD. Suppression of LPS-induced tau hyperphosphorylation by serum amyloid A. J Neuroinflammation. 2016;13:15. source
• Not checked yetcites [118] Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci. 2005;25:8843–53. source

In the paper

“Deficiency of FPR2 or administration of its inhibitors/anti-inflammatory ligands could alleviate the pathological symptoms of AD, including reduced activation of glial cells (microglia and/or astrocytes) and tau hyperphosphorylation, and ultimately leading to improvement in cognitive function [151–154].”

What the sources say

• Not checked yetcites [151] Medeiros R, Kitazawa M, Passos GF, Baglietto-Vargas D, Cheng D, Cribbs DH, LaFerla FM. Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice. Am J Pathol. 2013;182:1780–9. source
• Not checked yetcites [152] Zhang H, Wang D, Gong P, Lin A, Zhang Y, Ye RD, Yu Y. Formyl peptide receptor 2 deficiency improves cognition and attenuates tau hyperphosphorylation and astrogliosis in a mouse model of Alzheimer’s disease. J Alzheimers Dis. 2019;67:169–79. source
• Not checked yetcites [153] Schroder N, Schaffrath A, Welter JA, Putzka T, Griep A, Ziegler P, Brandt E, Samer S, Heneka MT, Kaddatz H, et al. Inhibition of formyl peptide receptors improves the outcome in a mouse model of Alzheimer disease. J Neuroinflammation. 2020;17:131. source
• Not checked yetcites [154] Trojan E, Tylek K, Schroder N, Kahl I, Brandenburg LO, Mastromarino M, Leopoldo M, Basta-Kaim A, Lacivita E. The N-formyl peptide receptor 2 (FPR2) agonist MR-39 improves ex vivo and in vivo amyloid beta (1–42)-induced neuroinflammation in mouse models of Alzheimer’s disease. Mol Neurobiol. 2021;58:6203–21. source

In the paper

“Interestingly, the R47H variant of TREM2, which is expressed by microglia and linked to innate immunity, has been found to present an altered glycosylation pattern and decreased stability compared with wild-type TREM2 [176], indicating a potential link between microglial neuroinflammation and glycosylation [177, 178].”

What the sources say

• Not checked yetcites [176] Park JS, Ji IJ, Kim DH, An HJ, Yoon SY. The Alzheimer’s disease-associated R47H variant of TREM2 has an altered glycosylation pattern and protein stability. Front Neurosci. 2016;10:618.
• Not checked yetcites [177] Haukedal H, Freude KK. Implications of glycosylation in Alzheimer’s disease. Front Neurosci. 2021;14:18. source
• Not checked yetcites [178] Rebelo AL, Chevalier MT, Russo L, Pandit A. Role and therapeutic implications of protein glycosylation in neuroinflammation. Trends Mol Med. 2022;28:270–89. source

In the paper

“Increases in tau O-GlcNAcylation inhibit tau aggregates and neuronal cell loss [174], indicating that O-GlcNAcylation modification can protect AD progression.”

What the sources say

• Not checked yetcites [174] Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, Vosseller K, Vocadlo DJ. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012;8:393–9. source

In the paper

“Overexpression of SAA by intracerebral injection attenuates tau hyperphosphorylation, and the mechanism is related to SAA-induced secretion of IL-10 from microglia [117].”

What the sources say

• Not checked yetcites [117] Liu J, Wang D, Li SQ, Yu Y, Ye RD. Suppression of LPS-induced tau hyperphosphorylation by serum amyloid A. J Neuroinflammation. 2016;13:15. source

In the paper

“The expression and activity of p300 are increased in the brain of AD patients [179], and the dysregulation of p300/CBP promotes tau acetylation, which could aggravate tau accumulation and pathology [46, 48].”

What the sources say

• Not checked yetcites [179] Aubry S, Shin W, Crary JF, Lefort R, Qureshi YH, Lefebvre C, Califano A, Shelanski ML. Assembly and interrogation of Alzheimer’s disease genetic networks reveal novel regulators of progression. PLoS ONE. 2015;10: e0120352. source
• Not checked yetcites [46] Min SW, Cho SH, Zhou YG, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010;67:953–66. source
• Not checked yetcites [48] Min SW, Chen X, Tracy TE, Li YQ, Zhou YG, Wang C, Shirakawa K, Minami SS, Defensor E, Mok SA, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015;21:1154. source

In the paper

“NLRP3 inflammasome has been proven to accumulate inside microglia upon activation, promoting cleavage and activity of caspase-1 and release of IL-1β [160].”

What the sources say

• Not checked yetcites [160] Heneka MT, McManus RM, Latz E. Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci. 2018;19:610–21. source

In the paper

“Abnormal acetylation of tau on lysine residues spans the microtubule-binding repeat region (MTBR), and this modification alone is sufficient to induce tau pathology and neurodegeneration [51].”

What the sources say

• Not checked yetcites [51] Shin M-K, Vazquez-Rosa E, Koh Y, Dhar M, Chaubey K, Cintron-Perez CJ, Barker S, Miller E, Franke K, Noterman MF, et al. Reducing acetylated tau is neuroprotective in brain injury. Cell. 2021;184:2715–32. source

In the paper

“Another study demonstrates that IL-10 deletion activates microglia, increases IL-6 production, and leads to tau hyperphosphorylation in response to acute systemic inflammation [165].”

What the sources say

• Not checked yetcites [165] Weston LL, Jiang S, Chisholm D, Jantzie LL, Bhaskar K. Interleukin-10 deficiency exacerbates inflammation-induced tau pathology. J Neuroinflammation. 2021;18:161. source

In the paper

“Cohen et al. reported that tau is a substrate of HDAC6, and the inhibition of HDAC6 increases tau acetylation [47].”

What the sources say

• Not checked yetcites [47] Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP, Trojanowski JQ, Lee VMY. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun. 2011;2:9. source

In the paper

“Our recent study identified that CMKLR1 deletion increases Aβ plaques in the AD mouse brain but reduces mortality and cognitive deficits of AD mice and attenuates tau hyperphosphorylation [14].”

What the sources say

• Not checked yetcites [14] Zhang HB, Lin AH, Gong P, Chen YQ, Ye RD, Qian F, Zhang Y, Yu Y. The chemokine-like receptor 1 deficiency improves cognitive deficits of AD mice and attenuates tau hyperphosphorylation via regulating tau seeding. J Neurosci. 2020;40:6991–7007. source

In the paper

“The expression of p47phox in neurons contributes to tau hyperphosphorylation directly, while p47phox in astrocytes affects tau hyperphosphorylation by activating astrocytes indirectly [13].”

What the sources say

• Not checked yetcites [13] Gong P, Chen YQ, Lin AH, Zhang HB, Zhang Y, Ye RD, Yu Y. p47(phox) deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD. Alzheimers Res Ther. 2020;12:18. source

In the paper

“In addition, tau also undergoes both N-linked glycosylation (N-glycosylation) [171] and O-linked N-acetylglucosaminylation (O-GlcNAcylation) [172], which have been proposed to affect tau phosphorylation and aggregation [173].”

What the sources say

• Not checked yetcites [171] Losev Y, Frenkel-Pinter M, Abu-Hussien M, Viswanathan GK, Elyashiv-Revivo D, Geries R, Khalaila I, Gazit E, Segal D. Differential effects of putative N-glycosylation sites in human Tau on Alzheimer’s disease-related neurodegeneration. Cell Mol Life Sci. 2021;78:2231–45. source
• Not checked yetcites [172] Zhu YP, Shan XY, Yuzwa SA, Vocadlo DJ. The emerging link between O-GlcNAc and Alzheimer disease. J Biol Chem. 2014;289:34472–81. source
• Not checked yetcites [173] Losev Y, Paul A, Frenkel-Pinter M, Abu-Hussein M, Khalaila I, Gazit E, Segal D. Novel model of secreted human tau protein reveals the impact of the abnormal N-glycosylation of tau on its aggregation propensity. Sci Rep. 2019;9:10. source

In the paper

“Inhibiting p300 with salsalate, a non-steroidal anti-inflammatory drug, could induce tau deacetylation, preserve tau axonal localization, and protect mice from neurodegeneration [51].”

What the sources say

• Not checked yetcites [51] Shin M-K, Vazquez-Rosa E, Koh Y, Dhar M, Chaubey K, Cintron-Perez CJ, Barker S, Miller E, Franke K, Noterman MF, et al. Reducing acetylated tau is neuroprotective in brain injury. Cell. 2021;184:2715–32. source

In the paper

“Selective suppression of p38α MAPK significantly reduces tau hyperphosphorylation and improves working memory in hTau mice [164].”

What the sources say

• Not checked yetcites [164] Maphis N, Jiang SY, Xu GX, Kokiko-Cochran ON, Roy SM, Van Eldik LJ, Watterson DM, Lamb BT, Bhaskar K. Selective suppression of the alpha isoform of p38 MAPK rescues late-stage tau pathology. Alzheimers Res Ther. 2016;8:54. source

In the paper

“However, with the failures or unsatisfactory efficacy of drugs anti-Aβ [9, 208–211], the development of drugs targeting other targets is increasing, such as anti-tau pathology and anti-neuroinflammation [212].”

What the sources say

• Not checked yetcites [9] Mullard A. FDA approval for Biogen’s aducanumab sparks Alzheimer disease firestorm. Nat Rev Drug Discov. 2021;20:496–496.
• Not checked yetcites [208] Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun XY, Thomas RG, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369:341–50. source
• Not checked yetcites [209] Jeremic D, Jimenez-Diaz L, Navarro-Lopez JD. Past, present and future of therapeutic strategies against amyloid-beta peptides in Alzheimer’s disease: a systematic review. Ageing Res Rev. 2021;72:36. source
• Not checked yetcites [210] Salloway S, Chalkias S, Barkhof F, Burkett P, Barakos J, Purcell D, Suhy J, Forrestal F, Tian Y, Umans K, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 2022;79:13–21. source
• Not checked yetcites [211] Mahase E. Aducanumab: European agency rejects Alzheimer’s drug over efficacy and safety concerns. BMJ. 2021;375:1.
• Not checked yetcites [212] Cummings J, Lee G, Nahed P, Kambar M, Zhong K, Fonseca J, Taghva K. Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement. 2022;8:24.

In the paper

“Overexpression of transcription factor EB (TFEB, a regulator of lysosomal biogenesis) in astrocytes promotes tau fibril species uptake and lysosomal activity as well as attenuates tau spreading and pathology in the hippocampus of P301S tauopathy mice [201] (Fig. 1).”

What the sources say

• Not checked yetcites [201] Martini-Stoica H, Cole AL, Swartzlander DB, Chen F, Wan YW, Bajaj L, Bader DA, Lee VMY, Trojanowski JQ, Liu ZD, et al. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J Exp Med. 2018;215:2355–77. source

In the paper

“Administration of NLRP3 inhibitor or ASC deficiency reduces the exogenously or non-exogenously seeded tau pathology, highlighting the promotion of NLRP3/ASC axis activation on the propagation of tau seeds [186].”

What the sources say

• Not checked yetcites [186] Stancu I-C, Cremers N, Vanrusselt H, Couturier J, Vanoosthuyse A, Kessels S, Lodder C, Brone B, Huaux F, Octave J-N, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019;137:599–617. source

In the paper

“Tau can bind to microglial CX3CR1 and initiate the internalization and degradation of tau [191].”

What the sources say

• Not checked yetcites [191] Castro-Sanchez S, Garcia-Yague AJ, Kugler S, Lastres-Becker I. CX3CR1-deficient microglia shows impaired signalling of the transcription factor NRF2: Implications in tauopathies. Redox Biol. 2019;22:12. source

In the paper

“In addition, several studies have shown that tau seeds taken up by microglia can activate microglia, further exacerbating tau propagation and pathology [186, 192, 193].”

What the sources say

• Not checked yetcites [186] Stancu I-C, Cremers N, Vanrusselt H, Couturier J, Vanoosthuyse A, Kessels S, Lodder C, Brone B, Huaux F, Octave J-N, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019;137:599–617. source
• Not checked yetcites [192] Jin MH, Shiwaku H, Tanaka H, Obita T, Ohuchi S, Yoshioka Y, Jin XC, Kondo K, Fujita K, Homma H, et al. Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation. Nat Commun. 2021;12:22. source
• Not checked yetcites [193] Wang C, Fan L, Khawaja RR, Liu BY, Zhan LH, Kodama L, Chin M, Li YQ, Le D, Zhou YG, et al. Microglial NF-kappa B drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun. 2022;13:19. source

In the paper

“Suppression of P2X purinoceptor 7 (P2RX7)-induced exosome secretion from microglia attenuates misfolded tau aggregates in the hippocampus and improves cognitive deficits of P301S mice [195].”

What the sources say

• Not checked yetcites [195] Ruan Z, Delpech JC, Venkatesan Kalavai S, Van Enoo AA, Hu J, Ikezu S, Ikezu T. P2RX7 inhibitor suppresses exosome secretion and disease phenotype in P301S tau transgenic mice. Mol Neurodegener. 2020;15:47. source

In the paper

“The integrin αV/β1 receptor interacts with tau monomers or fibrils and mediates tau uptake in primary astrocytes.”

What the sources say

• Not checked yetcites [203] Wang P, Ye YH. Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex. Nat Commun. 2021;12:95. source

In the paper

“Inhibitors of the O-GlcNAcase enzyme (OGA)-like thiamet G increase tau glycosylation, reduce NFTs and neuronal cell death, improve motor behavior, and prolong survival of tau transgenic mice [174, 220, 221].”

What the sources say

• Not checked yetcites [174] Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, Vosseller K, Vocadlo DJ. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012;8:393–9. source
• Not checked yetcites [220] Hastings NB, Wang X, Song L, Butts BD, Grotz D, Hargreaves R, Fred Hess J, Hong KK, Huang CR, Hyde L, et al. Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Mol Neurodegener. 2017;12:39. source
• Not checked yetcites [221] Permanne B, Sand A, Ousson S, Neny M, Hantson J, Schubert R, Wiessner C, Quattropani A, Beher D. O-GlcNAcase inhibitor ASN90 is a multimodal drug candidate for tau and alpha-synuclein proteinopathies. ACS Chem Neurosci. 2022;13:1296–314. source

In the paper

“These cholinesterase inhibitors and NMDA receptor antagonist memantine only temporarily relieve the symptoms of AD patients but do not delay the progression of the disease [206, 207].”

What the sources say

• Not checked yetcites [206] Sharma K. Cholinesterase inhibitors as Alzheimer’s therapeutics. Mol Med Rep. 2019;20:1479–87.
• Not checked yetcites [207] Kumar A, Singh A. Ekavali: a review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep. 2015;67:195–203. source

In the paper

“Various kinases are known to induce tau hyperphosphorylation, such as GSK-3β, a major tau kinase. These kinases are hyperactivated during the progression of AD and other tauopathies [19], indicating that the development of their mediators may be an effective treatment for these diseases.”

What the sources say

• Not checked yetcites [19] Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease. Acta Neuropathol. 2017;133:665–704. source

In the paper

“Tideglusib has been reported to reduce tau phosphorylation and has anti-inflammatory effects in animal models [216, 217].”

What the sources say

• Not checked yetcites [216] Sereno L, Coma M, Rodriguez M, Sanchez-Ferrer P, Sanchez MB, Gich I, Agullo JM, Perez M, Avila J, Guardia-Laguarta C, et al. A novel GSK-3beta inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009;35:359–67. source
• Not checked yetcites [217] Wang H, Huang S, Yan K, Fang X, Abussaud A, Martinez A, Sun HS, Feng ZP. Tideglusib, a chemical inhibitor of GSK3beta, attenuates hypoxic-ischemic brain injury in neonatal mice. Biochim Biophys Acta. 2016;1860:2076–85. source

In the paper

“The binding of tau fibrils to astrocyte αV/β1 activates integrin signaling, resulting in NF-κB activation, leading to an increase of pro-inflammatory cytokines and chemokines, and induction of expression of neurotoxic astrocytic markers [203].”

What the sources say

• Not checked yetcites [203] Wang P, Ye YH. Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex. Nat Commun. 2021;12:95. source

In the paper

“However, the treatment of this vaccine did not slow cognitive and functional decline in mild AD patients in the phase 2 clinical trial (ADAMANT, NCT02579252), although it shows the high immunogenicity [227].”

What the sources say

• Not checked yetcites [227] Novak P, Kovacech B, Katina S, Schmidt R, Scheltens P, Kontsekova E, Ropele S, Fialova L, Kramberger M, Paulenka-Ivanovova N, et al. ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nature aging. 2021;1:521–34. source

In the paper

“These findings suggest that phagocytized tau by astrocytes can be degraded and/or induce astrocytic activation.”

In the paper

“Jin et al. reported that microglia uptake exogenous monomeric tau in parallel via two surface receptors, LRP1 and TREM2, and then induce nuclear factor NF-κB activation in microglia through two different pathways, LRP1/polyglutamine binding protein 1 (PQBP1)/cyclic GMP–AMP synthase (cGAS)/Stimulator of interferon genes (STING) and TREM2/extracellular signal-regulated kinase (ERK)/Phosphoinositide”

What the sources say

• Not checked yetcites [192] Jin MH, Shiwaku H, Tanaka H, Obita T, Ohuchi S, Yoshioka Y, Jin XC, Kondo K, Fujita K, Homma H, et al. Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation. Nat Commun. 2021;12:22. source

In the paper

“The most likely reason for the failure of drugs targeting Aβ may be that Aβ pathology in AD does not always correlate with cognitive decline.”

In the paper

“This drug combination eliminates the senescent cells (also known as “senolytic therapy”), reduces tau pathology, amyloid load, and neuroinflammation, and ameliorates cognitive impairment in preclinical studies [256, 257].”

What the sources say

• Not checked yetcites [256] Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Misra Sen J, Gorospe M, Mattson MP. Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci. 2019;22:719–28. source
• Not checked yetcites [257] Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, Orr ME. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell. 2018;17: e12840. source

In the paper

“Accumulating evidence indicates that neuroinflammation may be the third pathological feature of AD and plays an integral role in AD pathogenesis and the promotion of cognitive impairment.”

In the paper

“While in the middle and late stages of AD, sustained and increased inflammatory responses in glial cells and neurons are pivotal cellular drivers and regulators of the exacerbation of tau pathology, further contributing to its worsening by promoting inflammatory responses.”

In the paper

“However, the efficacy of these drugs is controversial and needs further validation.”

In the paper

“A phase 2 clinical trial in 37 patients with mild to moderate AD (NCT02947893) showed that nilotinib was well-tolerated and reduced CSF pTau181 at 6 months compared to the placebo group [251].”

What the sources say

• Not checked yetcites [251] Turner RS, Hebron ML, Lawler A, Mundel EE, Yusuf N, Starr JN, Anjum M, Pagan F, Torres-Yaghi Y, Shi WK, et al. Nilotinib effects on safety, tolerability, and biomarkers in Alzheimer’s disease. Ann Neurol. 2020;88:183–94. source

In the paper

“The most likely reason for the failure of drugs targeting Aβ may be that Aβ pathology in AD does not always correlate with cognitive decline.”

In the paper

“A multi-center phase 2 clinical trial showed that although a 24-week treatment with neflamapimod did not ameliorate episodic memory in individuals with mild AD, neflamapimod treatment significantly reduces CSF total tau and tau phosphorylated at threonine 181 (pTau181) compared to the placebo group (NCT03402659).”

What the sources say

• Not checked yetcites NCT03402659