LABORATORY OF ANIMAL GENETICS AND MOLECULAR NEUROBIOLOGY

The main activity of our group is to develop disease models. We focus on cardiovascular disease (atherosclerosis), diabetes, neurodegeneration and psychiatric disorders. Mouse models provide excellent tools to study the pathomechanism of diseases in detail using genomics, proteomics, lipidomics, molecular biology, immunohistochemistry and electrophysiology. The major benefit of the animal models is their use in the development of effective drugs and therapies.

Modeling cardiovascular disease (atherosclerosis)

Cholesterol is transported in a lipoprotein-bound form in the blood. The four major transporter molecules are: high density lipoprotein (HDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Among these lipoproteins, LDL is highly prone to deposition in the intima of blood vessels initiating atherosclerosis. Apolipoprotein B (apoB) is a major structural component of LDL and VLDL, therefore, high plasma levels of apoB-containing lipoproteins are associated with an increased risk of coronary artery disease. The molecular and cellular mechanisms of the pathobiological changes that lead to the disease are still poorly understood. Accumulating evidence during recent years has led to the concept that subendothelial retention of apoB100-containing lipoproteins is the initial event in atherogenesis. This process might trigger local inflammation promoting vascular lesion formation.

We have developed hyperlipidemic mice by overexpressing the human apoB-100 gene in transgenic mice. These mice showed significantly elevated serum level of triglyceride when they were fed normal chow diet, and elevated serum cholesterol level when they were fed cholesterol-rich diet. Transgenic mice kept on cholesterol-rich diet developed atherosclerosis by the age of 6-7 months. In the heart of these animals increased cardiac superoxide and peroxinitrite formation was detected, which resulted in cardiac dysfunction (3).

Modeling age-related neurodegeneration

Recent studies show that the human neurodegenerative disorder, Alzheimer’s disease (AD) is accompanied by elevated apolipoprotein B concentration in the serum, and high serum level of apoB-100 modulates cerebral Aβ deposition in vivo. AD is characterized by progressive memory loss and cognitive impairment accompanied by neural degeneration, formation of amyloid plaques and neurofibrillary tangles. Abnormal accumulation of apolipoproteins and cholesterol in the brain of AD patients has been detected as core components of mature amyloid plaques. Cholesterol content in neuronal membranes contributes to the maintenance of neuronal plasticity and might directly modulate the rate of amyloid precursor protein (APP) processing. A disturbance or imbalance in the sterol metabolism has been found in AD and vascular dementia, evidenced by an increase in the cholesterol breakdown product 24S-hydroxycholesterol. It was recently demonstrated that elevation of plasma triglyceride level precedes amyloid deposition in Alzheimer’s disease model mice. Although apolipoprotein and cholesterol research was previously mainly focusing on cardiovascular diseases, the latest findings indicate that apoB-100 might be involved in the development of stroke and neurodegenerative processes.

Investigating the phenotype of apoB-100 transgenic mice we found that vascular lesions affect not only the cardiovascular but also the cerebrovascular system. ApoB-100 overexpression induced alterations in the cerebral protein profile of transgenic mice, an approximately two-fold increase in the level of signaling proteins involved in apoptosis, nonreceptor tyrosine kinase Pyk2, p38MAPK, MAPK (mitogen activated protein kinase) and brain “injury indicator” proteins (nNOS, iNOS, S-100 β, glutamine synthetase, and cellular stress protein, Hsp70) were detected (2). Morphological analysis using MRI and MEMRI revealed a large increase in the cavity size of the lateral and dorsal ventricles and a moderate enlargement of the aqueduct (fourth ventricle) in the brain of heterozygous transgenic animals (2). Moreover, the enlargement of the ventricular system was transgene dose-dependent, which is more pronounced in homozygous than in heterozygous transgenic mice (See fig. below).