Human misfolded truncated tau protein promotes activation of microglia and leukocyte infiltration in the transgenic rat model of tauopathy

https://doi.org/10.1016/j.jneuroim.2009.01.013Get rights and content

Abstract

It has been hypothesized that misfolded tau protein could be a mediator of the inflammatory response in human tauopathies. Here we show that neurodegenerative lesions caused by human truncated tau promote inflammatory response manifested by upregulation of immune-molecules (CD11a,b, CD18, CD4, CD45 and CD68) and morphological activation of microglial cells in a rat model of tauopathy. In parallel, the innate immune brain response promotes activation of MHC class II positive blood-borne leukocytes and their influx into the brain parenchyma. These findings have important consequences for the rationale drug development of effective inflammation-based therapeutic strategies for human tauopathies.

Introduction

Neuroinflammation plays a fundamental role in the progression of Alzheimer's disease (AD) and other tauopathies (McGeer and McGeer, 1995, McGeer and McGeer, 2004, Lukiw and Bazan, 2000, Wyss-Coray and Mucke, 2002, Mrak and Griffin, 2005). It may be triggered by the accumulation of misfolded proteins released from injured neurons and synapses (Wyss-Coray and Mucke, 2002). In Alzheimer's disease, neuroinflammation includes a wide spectrum of inflammatory molecules such as cytokines and chemokines, the proteins of the classical and alternative complement pathways, the acute-phase reactants, peroxisomal proliferators-activated receptors, components of the coagulation pathways, proteoglycans, cathepsins and cystatins, heat shock proteins, the metallomatrix proteinases and intercellular adhesion molecules (McGeer and McGeer, 1999, McGeer and McGeer, 2002, Tuppo and Arias, 2005). It is well documented that extracellular aggregates of beta amyloid (Aβ), which senile plaques are comprised of, are considered to be responsible for initiating the non-immune mediated chronic inflammatory response manifested by activated microglia and astrocytes (Akiyama et al., 2000, Mrak and Griffin, 2001, Walsch and Aisen, 2004, Eikelenboom et al., 2006). Beta amyloid deposits attract microglia and activate them to produce acute-phase proteins, complement components, cytokines and chemokines (Blasko and Grubeck-Loebenstein, 2003, Blasko et al., 2004). On the other hand, the plaque-associated microglia are considered an important element in the degradation of Aβ and transformation of early diffuse amyloid deposits into the late neuritic Aβ plaques (Mrak and Griffin, 2005, Tuppo and Arias, 2005, Rogers et al., 2002, D'Andrea et al., 2004).

Activated microglia are also present on and around neurofibrillary tangles at early (Sheng et al., 1997) as well as at later stages of tangle formation (Cras et al., 1991, Perlmutter et al., 1992, Dickson et al., 1996, DiPatre and Gelman, 1997, Oka et al., 1998, Overmyer et al., 1999, Sheffield et al., 2000). Further, it has been demonstrated that microglial activation was also correlated with tau burden in other human tauopathies such as tangle-predominant dementia, Guam parkinsonism dementia, progressive supranuclear palsy and corticobasal degeneration (Schwab et al., 1996, Ishizawa and Dickson, 2001, Imamura et al., 2001). Although activation of microglia linked to tau deposition has been documented in mice transgenic for human mutant tau protein (Bellucci et al., 2004, Yoshiyama et al., 2007), little is known about the inflammatory immunomolecules involved in this response. In order to decipher the pattern of neuroinflammation promoted by tau neurodegeneration, we used rats transgenic for human truncated tau protein, exhibiting characteristic features of human tauopathies including neurofibrillary tangles and progressive axonopathy (Zilka et al., 2006). These pathological changes were associated with functional impairment characterized by a variety of neurobehavioural symptoms (Hrnkova et al., 2007). In the present study we tested: a) the hypothesis that neurofibrillary lesions induced by human truncated tau protein may stimulate inflammatory response; b) what immunophenotypic profile of inflammatory cells is characteristic of this process and c) whether blood born leukocytes take part in tau induced inflammatory response.

Section snippets

Transgene construct and generation of transgenic animals

The transgene construct was prepared by cloning a truncated human tau cDNA encoding amino acids 151–391 into the mouse Thy-1 gene immediately downstream of the brain promoter/enhancer sequence. The ATG codon follows immediately after the Ban I site at the end of the brain enhancer. The original Thy-1 gene sequence coding for exons II to IV, together with the thymus enhancer sequence was replaced by the human cDNA sequence. The cloned construct was introduced into DH5α bacteria and amplified.

Activated microglia are distributed in the brain area affected by neurofibrillary degeneration in rats transgenic for human truncated tau protein

The aim of this study was to analyze whether human truncated tau might induce inflammatory response and to identify the inflammatory pattern of this response. In order to detect and localize neurofibrillary degeneration and microglial activation, paraffin sagittal sections were prepared from control and transgenic rat brains. Neurofibrillary lesions were detected using antibody AT8, which recognizes tau phosphorylated at Ser-202, Thr-205 (Braak et al., 1994, Goedert et al., 1995). Activated

Discussion

We previously showed that non-mutated human truncated tau derived from sporadic Alzheimer's disease is able to induce and drive neurofibrillary degeneration in rats when expressed as transgene (Zilka et al., 2006, Koson et al., 2008). Transgenic rats displayed the AD-characteristic tau cascade consisting of tau hyperphosphorylation, formation of neurofibrillary tangles (NFT), sarcosyl-insoluble tau complexes and axonal degeneration. These pathological changes led to the progressive decline of

Acknowledgement

This work was supported by research grants APVV-0631-07, LPP-0326-06, LPP-0353-06, LPP-0354-06 and LPP-0363-06. The authors wish to thank Assoc. Prof. Colin Campbell, PhD., University of Minnesota, USA, for advice and careful reading of the manuscript.

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