Lipopolysaccharide-Induced Inflammation Exacerbates Tau Pathology by a Cyclin-Dependent Kinase 5-Mediated Pathway in a Transgenic Model of Alzheimer's Disease

By M. Kitazawa, S. Oddo, T. R. Yamasaki, K. Green, F. LaFerla. Journal of Neuroscience, 2005

671 citations recorded by the source corpus.

Inflammation is a critical component of the pathogenesis of Alzheimer's disease (AD). Although not an initiator of this disorder, inflammation nonetheless plays a pivotal role as a driving force that can modulate the neuropathology. Here, we characterized the time course of microglia activation in the brains of a transgenic model of AD (3xTg-AD) and discerned its relationship to the plaque and tangle pathology. We find that microglia became activated in a progressive and age-dependent manner, and this activation correlated with the onset of fibrillar amyloidβ-peptide plaque accumulation and tau hyperphosphorylation. To determine whether microglial activation can exacerbate the pathology, we exposed young 3xTg-AD mice to lipopolysaccharide (LPS), a known inducer of CNS inflammation. Although amyloid precursor protein processing appeared unaffected, we find that LPS significantly induced tau hyperphosphorylation at specific sites that were mediated by the activation of cyclin-dependent kinase 5 (cdk5) through increased formation of the p25 fragment. We further show that administration of roscovitine, a selective and potent inhibitor of cdk5, markedly blocked the LPS-induced tau phosphorylation in the hippocampus. Therefore, this study clearly demonstrates that microglial activation exacerbates key neuropathological features such as tangle formation.

Subfields: Molecular Biology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/f8bc048f1f83fcdbed972f0f9ebff8f90eeae8fb

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Michael T. Heneka
2. Jin-Tai Yu
3. B. West
4. C. Cunningham
5. L. Tan
6. F. LaFerla
7. R. Ransohoff

In Neurology

1. R. Ransohoff
2. Michael T. Heneka
3. C. Cunningham
4. M. O’Banion
5. A. Cardona
6. Wen-Ying Wang
7. Jin-Tai Yu
8. M. Tan

In Physiology

1. R. Ransohoff
2. Michael T. Heneka
3. M. O’Banion
4. Wen-Ying Wang
5. Jin-Tai Yu
6. C. Cunningham
7. M. Tan
8. L. Tan

Citations in the corpus

• Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. (2016, background): “…a key feature of the Alzheimer’s disease brain (Fillit et al., 1991; Ishizuka et al., 1997; McGeer and McGeer, 1999; Cagnin et al., 2001; Dandrea et al., 2001), as well as being prominently observed in amyloid precursor protein (APP) overexpressing transgenic mouse models (Kitazawa et al., 2005).”
• Microglia and neurodegeneration: The role of systemic inflammation (2013, background): “In the triple transgenic model of AD, LPS treatment increased the severity of Tau tangle pathology when administered at 500 lg/kg twice weekly for 6 weeks (Kitazawa et al., 2005).”
• Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. (2015, background): “In support of this, previous study has revealed that transgenic mice inducing neuroinflammation by injecting LPS triggered intracellular Aβ deposition (43,44) and tau phosphorylation (45) in the brain.”
• Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “Abbreviations AD: Alzheimer’s disease; APOE: Apolipoprotein E; Aβ: β-Amyloid; APP: Amyloid precursor protein; KCC2: K-Cl cotransporter 2; GABA : γaminobutyric acid; sAPP: Soluble amyloid precursor proteins; CNS: Central nervous system; PS1/2: Presenilins 1/2; CSF: Cerebral spinal fluid; LRP1: Lowden”
• Identification of miRNA Changes in Alzheimer's Disease Brain and CSF Yields Putative Biomarkers and Insights into Disease Pathways (2008, neutral): “of AD [33,39,63].”
• Glucocorticoids Increase Amyloid-β and Tau Pathology in a Mouse Model of Alzheimer’s Disease (2006, background): “We reported previously that activated microglia associate with extracellular A plaques in the 3 Tg-AD from 12 months of age (Kitazawa et al., 2005).”
• Inflammatory processes in Alzheimer's disease. (2007, positive): “These changes in tau were associated with increased levels of IL1β and appeared to result from activation of cdk5 kinase (Kitazawa et al., 2005).”
• Regulation of Tau Pathology by the Microglial Fractalkine Receptor (2010, positive): “Finally, consistent with the findings in the 3xTg mouse model, LPS administration to hTau mice induced enhanced MAPT phosphorylation (Kitazawa et al., 2005).”
• Inflammation as a central mechanism in Alzheimer's disease (2018, background): “[79] Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM.”