Research - Institute of Biochemistry - Neurobiology Unit - Laboratory of Animal Genetics and Molecular Neurobiology

senior research associate

Erzsébet Melinda TÓTH research associate
Brigitta DUKAY Ph.D. student
Lászlóné KIS-SEBESTYÉN laboratory assistant
Tímea MÁRKUS-VADÓC laboratory assistant


Our research focuses on the development of mouse models of human diseases, such as cardiovascular diseases and neurodegenerative disorders.

Previously, we generated transgenic mice overexpressing the human ApoB-100 protein. We have shown, that these mice are hyperlipidemic and hyperlipidemia induces atherosclerosis, myocardial oxidative and nitrosative stress leading to cardiovascular failure in transgenic mice (Csont et al. 2007). However, we have observed that, overexpression of ApoB-100 affects not only the cardiovascular system, but the cerebrovascular system as well, since the density of cortical microcapillary network is significantly reduced in ischemic transgenic brains compared to wild-types (Süle et al. 2009). We detected increased perivascular accumulation of ApoB-100 and enhanced lipid peroxidation in the cortex and hippocampus of transgenic mice (Löffler et al. 2013). In parallel, we demonstrated impairment of presynaptic (Lénárt et al. 2012) and cognitive functions (Löffler et al. 2013) in transgenic brains using electrophysiology and behavioral tests, respectively. The antibody microarray experiment revealed upregulation of several cytoskeletal proteins and proteins involved in oxidative stress and apoptosis in the brain lysates of transgenic mice (Bereczki et al. 2008). We detected increased phosphorylation of tau proteins (primarily at Ser262, Ser396, Ser199/202, Ser404 phosphosites) in the hippocampus and cortex of ApoB-100 transgenic mice, which resulted in disruption of neurotubular network and eventually led to the degeneration of neurons (Bereczki et al. 2008 and Lénárt et al. 2012). Massive neurodegeneration was also demonstrated in the brain of transgenic mice using MRI and MEMRI imaging (Bereczki et al 2008. Fig.1.). These results strengthen our hypothesis that overexpression of ApoB-100 protein might lead to the development of neurodegeneration.

In another set of experiments we demonstrated the neuroprotective role of a small heat-shock protein, hsp27. Using several behavioral tests (footprint analysis, balance beam walking, inverted screen test, swimming test) we showed that after acut alcohol administration (2g/kg ip.) hsp27 excess improves motor coordination and ataxia (Toth et al. 2010). After chronic alcohol consumption (20% ethanol solution for 5 weeks) overexpression of hsp27 significantly reduces the number of apoptotic neurons in the hippocampus, cortex and cerebellum of transgenic mice (Toth et al. 2010).

To study the effect of Hsp27 on amyloid-ß (Aß) accumulation, synaptic and memory functions and neurodegeneration, we generated transgenic mice overexpressing human Hsp27 protein and crossed with APPswe/PS1dE9 mouse strain, a mouse model of Alzheimer's disease (AD). Using anti-amyloid antibody, we counted significantly less amyloid plaques in the brain of APPswe/PS1dE9/Hsp27 animals compared to AD model mice (Toth et al. 2013). Electrophysiological recordings have shown that excitability of neurons was significantly increased and long-term potentiation (LTP) was impaired in AD model mice, whereas they were normalized in Hsp27 overexpressing AD model mice. Finally, using a set of different behavioral tests, we found that spatial learning was impaired in AD model mice however, it was rescued by Hsp27 overexpression (Toth et. al. 2013). These results suggest that overexpression of Hsp27 protein might ameliorate certain symptoms of AD.

Figure 1. MRI images show enlargement of the third and lateral ventricules in heterozygote (+/-) and homozygote (+/+) apoB-100 transgenic mice compared to wild type (-/-) mice.

Selected publications

Várhelyi ZP, Kálmán J, Oláh Z, Ivitz EV, Fodor EK, Sántha M, Datki ZL, Pákáski M. 2017. Adiponectin Receptors Are Less Sensitive to Stress in a Transgenic Mouse Model of Alzheimer's Disease. Front Neurosci. 2017 Apr 11;11:199. doi: 0.3389/fnins.

Kasza Á, Hunya Á, Frank Z, Fülöp F, Török Z, Balogh G, Sántha M, Bálind Á, Bernáth S, Blundell KL, Prodromou C, Horváth I, Zeiler HJ, Hooper PL, Vigh L, Penke B. 2016. Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer's Disease. J Alzheimer’s Dis. 53(2):557-71.

Löffler T, Schweinzer C, Flunkert S, Sántha M, Windisch M, Steyrer E, Hutter-Paier B.2016. Brain cortical cholesterol metabolism is highly affected by human APP overexpression in mice. Mol Cell Neurosci. 74:34-41.

Lénárt N, Walter FR, Bocsik A, Sántha P, Tóth ME, Harazin A, Tóth AE, Vizler C, Török Z, Pilbat AM, Vígh L, Puskás LG, Sántha M, Deli MA. 2015. Cultured cells of the blood–brain barrier from apolipoprotein B-100 transgenic mice: effects of oxidized low-density lipoprotein treatment. Fluids and Barriers of the CNS 12 (1), 1-16.

Zádor F, Lénárt N, Csibrány B, Sántha M, Molnár M, Tuka B, Samavati R, Klivényi P, Vécsei L, Marton A, Vizler C, Nagy GM, Borsodi A, Benyhe S, Páldy E. 2015. Low dosage of rimonabant leads to anxiolytic-like behavior via inhibiting expression levels and G-protein activity of kappa opioid receptors in a cannabinoid receptor independent manner. Neuropharmacology 89, 298-307.

Oláh Z., J Kálmán, ME Tóth, Á Zvara, M Sántha, E Ivitz, Z Janka, M Pákáski. 2015. Proteomic Analysis of Cerebrospinal Fluid in Alzheimer’s Disease: Wanted Dead or Alive. Journal of Alzheimer's disease: J. Alzheimer’s Disease 44 (4), 1303-1312.

Tóth, ME, M Sántha, B Penke, L Vígh . 2015. How to stabilize both the proteins and the membranes: Diverse effects of sHsps in neuroprotection. The Big Book on Small Heat Shock Proteins, 527-562.

Su Q, Baker C, Christian P, Naples M, Tong X, Zhang K, Santha M, Adeli K.2014. Hepatic mitochondrial and ER stress induced by defective PPARα signaling in the pathogenesis of hepatic steatosis. American Journal of Physiology-Endocrinology and Metabolism 306 (11), E1264.

Tóth ME, Vígh L, Sántha M. 2014. Alcohol stress, membranes, and chaperones. Cell Stress Chaperones19:299-309.