6 October 2005. 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.
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 Neuroscience. 2005 September 28; 25:8843–8853. Abstract