Microglia don’t start the fire in Alzheimer disease brain, but they certainly can heat things up when it comes to hyperphosphorylation of tau. That’s the conclusion of a study from Frank LaFerla’s lab at the University of California at Irvine which looked at microglia activation and the progression of plaque and tangle pathology in their triple transgenic AD mice. The work, published in the September 28 Journal of Neuroscience, shows that kicking off inflammation by giving mice lipopolysaccharide (LPS) causes microglia activation and increased tau phosphorylation. The tau effects are mediated by CDK5 activation, showing that inflammation can increase tangle pathology via CDK5.

To pin down the role of inflammation in the progression of AD, first author Masashi Kitazawa and colleagues surveyed microglia activation in APP/PS1/tau triple transgenic mice. Previously, the same lab has shown age-dependent plaque and tangle formation in these mice, along with learning and behavior deficits (see ARF related news story and Billings et al., 2005). Young mice (4-9 months) had no activation of microglia despite intraneuronal Aβ accumulation and some diffuse plaque formation. The first CDK5-positive activated microglia appeared around 12 months of age, at the time when fibrillar Aβ deposits were becoming prevalent. Microglial activation continued to go up as the age-related amyloid burden increased between 12 and 24 months. At that time, microglia were observed clustered around fibrillar thioflavin S-positive plaques, similar to the situation in human AD brain. The time course suggests that build-up of extraneuronal Aβ is a major trigger for the onset of inflammation, which occurs relatively late in the scheme of things.

To look at the ramifications of inflammation on plaque or tangle pathology, the researchers took another approach, injecting young mice (4 months) repeatedly with LPS over a 6-week period to stimulate a generalized inflammatory response. This regimen caused an increase in activated microglia to levels normally seen in the older animals, and a fivefold increase in brain interleukin-1 content.

The increase in inflammatory cells and cytokines did not alter levels of amyloid precursor protein (APP), or Aβ peptides in the young mice. But LPS treatment did alter tau phosphorylation. Normally, the transgenic mice start to show tau hyperphosphorylation at 1 year, but the 6-month-old LPS-treated mice had clear evidence of hyperphosphorylated tau in the hippocampus. Using a variety of phospho-specific antibodies to tau, the authors showed that hyperphosphorylation was occurring at selected sites consistent with the action of a specific kinase. When they went looking for the kinase, it turned out to be neither the IL-1-activated p38 MAP kinase nor JNK kinase, but instead was CDK5.

In LPS-treated mice, CDK5 protein levels were unchanged, but levels of the kinase activator p25 were elevated and CDK5 activity in brain was doubled. Excess p25 has been previously implicated in both tau hyperphosphorylation and Aβ pathology (see ARF related news story). These new results link the activation of microglia, either by amyloid plaques or by LPS, to this same pathway, and suggest at least one way in which inflammation may work to fan the flames of neuropathology.—Pat McCaffrey


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  1. Epidemiological studies indicate that populations taking anti-inflammatory drugs have a significantly reduced prevalence of AD, or a slower mental decline (McGeer et al., 1998). This paper demonstrated how inflammation due to microglial activation might affect tau pathology through Aβ. Aβ deposition activates microglia, which then enhanced an inflammatory response. The authors reported that LPS-evoked inflammation induced tau phosphorylation by activating CDK5, which in turn follows from increasing the level of CDK5 activator p25. Taken together with the epidemiological study, tau appears to play a crucial role in AD and in the rate of mental decline during the disease.

    The authors also write that the accumulation of p25 by LPS treatment that they observed is similar to observations of p25 accumulation in AD brain. They showed that LPS induced the accumulation of p25, and tau phosphorylation in non-Tg mouse. However, this accumulation is still controversial. Some reports showed no difference of p25 level between AD and non-AD (Taniguchi et al., 2001; Takashima et al., 2001; Tandon et al., 2003). If Aβ deposition was responsible for microglial activation and inflammatory response, then APP Tg mouse strains would also show CDK5 activation and tau phosphorylation. Yet, this phenomenon has not yet been reported. Whether the accumulation of p25 and tau phosphorylation are LPS-specific or inflammation-related phenomena, therefore, remains an open question.

    Indeed, CDK5 is a tau kinase. p25 was first purified from microtubule fractions of bovine brain and the complex CDK5/p25 was isolated and named tau protein kinase II (TPKII) (Ishiguro et al., 1992). In vitro tau phosphorylation studies showed that CDK5/p25 could phosphorylate tau to the normal phosphorylation state (Arioka et al., 1993), not to the hyperphosphorylated state that can lead to pathology. The synergistic involvement of other kinases, therefore, is required to form PHF-tau. The authors’ claims that CDK5 activation alone forms neurofibrillary tanges will be convincing once the results of in vitro tau phosphorylation studies can support them.

    View all comments by Akihiko Takashima
  2. Elevated p25 is thought to account for increased or pathological CDK5 activation that seems to be a commonality in several human neurodegenerative diseases. However, it is not yet understood how so many different etiologies lead to this common step in CDK5 activation, or how CDK5 participates in the unique pathological landscapes in the different diseases. Although it is widely accepted that environmental factors play a significant role in regulating the onset and progression of neurodegenerative diseases, this study by Kitazawa et al. provides tangible evidence for a link between inflammation and p25-induced CDK5 activation in the triple transgenic AD mouse.

    Curiously, activation of CDK5 by the inflammatory agent lipopolysaccharide (LPS) had no impact on amyloid pathology but enhanced phosphorylation of tau at specific sites. This enhanced phosphorylation of tau was blocked by the pan-CDK inhibitor, roscovitine, supporting the idea that LPS-induced tau hyperphosphorylation is mediated by CDK5. This study opens the way to exploring a wide variety of immune-mediated mechanisms in regulation of brain CDK5 activity and perhaps neurodegenerative pathology. Because of the broad specificity of roscovitine, molecular identification of the relevant CDK(s) will need to be pursued.


News Citations

  1. San Diego: Treating Forgetfulness—Triple Transgenics Provoke
  2. Tangles, Neurodegeneration, Plaques—p25 Does it All

Paper Citations

  1. . Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron. 2005 Mar 3;45(5):675-88. PubMed.

Further Reading


  1. . Role of protein kinases in neurodegenerative disease: cyclin-dependent kinases in Alzheimer's disease. Front Biosci. 2005 Jan 1;10:143-59. PubMed.
  2. . Interaction of Tau with Fe65 links tau to APP. Neurobiol Dis. 2005 Mar;18(2):399-408. PubMed.
  3. . Cyclin-dependent kinase inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick Type C mice. Am J Pathol. 2004 Sep;165(3):843-53. PubMed.

Primary Papers

  1. . 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 Sep 28;25(39):8843-53. PubMed.