Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Oct 12:7:64.
doi: 10.1186/1742-2094-7-64.

Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease

Zuzana Stozicka  1 , Norbert Zilka, Petr Novak, Branislav Kovacech, Ondrej Bugos, Michal Novak
Affiliations

Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease

Zuzana Stozicka et al. J Neuroinflammation. .

Abstract

Background: Numerous epidemiological studies demonstrate that genetic background modifies the onset and the progression of Alzheimer's disease and related neurodegenerative disorders. The efficacious influence of genetic background on the disease pathway of amyloid beta has been meticulously described in rodent models. Since the impact of genetic modifiers on the neurodegenerative and neuroinflammatory cascade induced by misfolded tau protein is yet to be elucidated, we have addressed the issue by using transgenic lines expressing the same human truncated tau protein in either spontaneously hypertensive rat (SHR) or Wistar-Kyoto (WKY) genetic background.

Methods: Brains of WKY and SHR transgenic rats in the terminal stage of phenotype and their age-matched non-transgenic littermates were examined by means of immunohistochemistry and unbiased stereology. Basic measures of tau-induced neurodegeneration (load of neurofibrillary tangles) and neuroinflammation (number of Iba1-positive microglia, their activated morphology, and numbers of microglia immunoreactive for MHCII and astrocytes immunoreactive for GFAP) were quantified with an optical fractionator in brain areas affected by neurofibrillary pathology (pons, medulla oblongata). The stereological data were evaluated using two-way ANOVA and Student's t-test.

Results: Tau neurodegeneration (neurofibrillary tangles (NFTs), axonopathy) and neuroinflammation (microgliosis, astrocytosis) appeared in both WKY and SHR transgenic rats. Although identical levels of transgene expression in both lines were present, terminally-staged WKY transgenic rats displayed significantly lower final NFT loads than their SHR transgenic counterparts. Interestingly, microglial responses showed a striking difference between transgenic lines. Only 1.6% of microglia in SHR transgenic rats expressed MHCII in spite of having a robust phagocytic phenotype, whereas in WKY transgenic rats, 23.2% of microglia expressed MHCII despite displaying a considerably lower extent of transformation into phagocytic phenotype.

Conclusions: These results show that the immune response represents a pivotal and genetically variable modifying factor that is able to influence vulnerability to neurodegeneration. Therefore, targeted immunomodulation could represent a prospective therapeutic approach to Alzheimer's disease.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Back-crossed WKY TG rats show the basic features of the WKY strain. Rats of the WKY TG line in the F5 generation demonstrated morphological features of the WKY strain, including elongated skull shape (A) and increased body size (C), compared to SHR rats (B, D). Systolic blood pressure measurements show chronic hypertension in SHR controls and SHR TG rats, and confirm normal blood pressure in WKY controls as well as in the back-crossed WKY TG line (E). The influence of genetic background factor on systolic blood pressure is highly significant (two-way ANOVA, F = 166.85, *** p < 0.0001), but transgenic factor (F = 1.14, p = 0.30) or their interaction (F = 0.2, p = 0.66) does not influence the blood pressure of the rats. Transgene expression (measured as ratio of human misfolded to rat endogenous tau) is almost identical in the brains of SHR TG and WKY TG rats (F).
Figure 2
Figure 2
Qualitative and quantitative profile of neurofibrillary pathology in two transgenic rat models of human tauopathy. NFTs show similar morphological and immunohistochemical features in both transgenic lines - WKY TG (A, C) and SHR TG (B, D). Neurofibrillary tangles were stained by Gallyas silver staining (A, B, reticular nuclei) and immunolabeled with antibody AT8 recognizing tau phosphorylated at Ser202 and Thr205 (C, D, reticular nuclei). Phosphorylated tau is also distributed in neuronal processes, resulting in axonopathy visible in the white matter (E, F). The number of NFTs was stereologically quantified in brainstem (pons and medulla oblongata) as a region of interest (G). Stereological analysis revealed significantly lower number of NFTs in WKY TG rats compared to SHR TG rats (H, Student's t-test, * p < 0.05). Pre-fixed frozen sections. Scale bars: 50 μm.
Figure 3
Figure 3
Qualitative profile of activated microglia in two transgenic rat models of human tauopathy. Microglia in brainstem of WKY TG (A, C, E) as well as SHR TG (B, D, F) rats show increased expression of activation markers. Large number of microglia strongly immunoreactive for CD11b/CD18 (complement 3 receptor) (A, B) demonstrate the involvement of complement system in the tau-induced neuroinflammation. CD4 co-receptor is usually present on T-cells interacting with MHCII-positive antigen presenting cells; in tau-induced neuroinflammation it is increased mainly on microglia/macrophages (C, D). Round-shaped cell parts positive for CD68 (lysosomal membrane glycoprotein) indicate putative phagocytosis (E, F). Post-fixed (A, B, C, D) and pre-fixed (E, F) frozen sections. Scale bars: 50 μm.
Figure 4
Figure 4
Qualitative and quantitative profile of activated microglia in two transgenic rat models of human tauopathy. Prominent microgliosis was observed by immunohistochemical staining with Iba1 antibody in both transgenic lines - WKY TG (A) and SHR TG (B) - compared to non-transgenic WKY (C) and SHR (D) age-matched controls. Stereological quantification revealed that the numbers of Iba1-positive microglia/macrophages in brainstem of both transgenic lines doubled in comparison with non-transgenic controls (G, two-way ANOVA, transgenic factor, *** p < 0.0001). There is also a tendency to a higher number of Iba-1 positive microglia in SHR TG rats compared to WKY TG. The morphology of microglia in brainstem of transgenic rats indicates a high level of activation including presumptive phagocytosis (E, F - arrows). In SHR TG rats, there are significantly more microglia showing phagocyte-like morphology than in WKY TG (H, two-way ANOVA, transgenic factor, *** p < 0.0001, genetic background factor, ** p = 0.001). Pre-fixed frozen sections. Scale bars: 50 μm for A-D, 20 μm for E, F.
Figure 5
Figure 5
Expression of MHC class II molecules is different in brains of transgenic rat models. In brainstem of WKY TG rats (A), activation of microglia is accompanied by widespread MHCII expression, while in SHR TG (B), only sparse MHCII staining was recorded. Stereological quantification shows highly significant differences between the transgenic lines. In WKY TG rats, there are 10 times more microglia that express MHCII than are present in SHR TG rats (C, Studen't t-test, *** p < 0.001). Pre-fixed frozen sections. Scale bars: 50 μm.
Figure 6
Figure 6
Qualitative and quantitative profile of activated astroglia in two transgenic rat models of human tauopathy. There is an approximately 25% increase in GFAP-positive astrocytes in brainstem in both transgenic lines (A - WKY TG, B - SHR TG) compared to age-matched controls (C - WKY crl, D - SHR crl). Morphological signs of astrocytic activation and hypertrophy (E) are observed in the brainstems of both transgenic rat lines. Stereological quantification (F) reveals no significant differences between WKY TG and SHR TG rats in numbers of GFAP-positive astrocytes. However, the difference in numbers of GFAP-positive astrocytes between transgenic and control rats is highly significant (two-way ANOVA, transgenic factor *** p < 0.0001). Pre-fixed frozen sections. Scale bars: 50 μm for A-D, 20 μm for E.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Elbaz A, Dufouil C, Alpérovitch A. Interaction between genes and environment in neurodegenerative diseases. C R Biol. 2007;330:318–328. doi: 10.1016/j.crvi.2007.02.018. - DOI - PubMed
    1. Reitz C, Mayeux R. Use of genetic variation as biomarkers for Alzheimer's disease. Ann N Y Acad Sci. 2009;1180:75–96. doi: 10.1111/j.1749-6632.2009.04945.x. - DOI - PMC - PubMed
    1. Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer's disease: inflammation, cholesterol, and misfolded proteins. Lancet. 2004;363:1139–1146. doi: 10.1016/S0140-6736(04)15900-X. - DOI - PubMed
    1. Kivipelto M, Helkala E-L, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, Soininnen H, Tuomilehto J, Nissien A. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, Soininnen H, Tuomilehto J, Nissien A. BMJ. 2001;322:1447–14451. doi: 10.1136/bmj.322.7300.1447. - DOI - PMC - PubMed
    1. Stozicka Z, Zilka N, Novak M. Risk and protective factors for sporadic Alzheimer's disease. Acta Virol. 2007;51:205–222. - PubMed

Publication types

MeSH terms