. 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.

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  1. 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.

    View all comments by Inez Vincent
  2. 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.

    References:

    . The importance of inflammatory mechanisms in Alzheimer disease. Exp Gerontol. 1998 Aug;33(5):371-8. PubMed.

    . Calpain-mediated degradation of p35 to p25 in postmortem human and rat brains. FEBS Lett. 2001 Jan 26;489(1):46-50. PubMed.

    . Involvement of cyclin dependent kinase5 activator p25 on tau phosphorylation in mouse brain. Neurosci Lett. 2001 Jun 22;306(1-2):37-40. PubMed.

    . Brain levels of CDK5 activator p25 are not increased in Alzheimer's or other neurodegenerative diseases with neurofibrillary tangles. J Neurochem. 2003 Aug;86(3):572-81. PubMed.

    . Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. J Biol Chem. 1992 May 25;267(15):10897-901. PubMed.

    . Tau protein kinase II is involved in the regulation of the normal phosphorylation state of tau protein. J Neurochem. 1993 Feb;60(2):461-8. PubMed.

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