Institutional creator:

Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN

Contributor:

Strosznajder, Joanna B. (Promotor)

Publisher:

Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN

Description:

Bibliografia zawiera 365 pozycji ; 169 s.: il, wykr., tabl.; 30 cm.

Degree name:

doktor

Level of degree:

2

Degree discipline :

medical sciences

Degree grantor:

Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN

Type of object:

Praca dyplomowa

Abstract:

Alzheimer's disease (AD) is a neurodegenerative disease and the most severe form of dementia.The key neuropathological hallmarks in the brain are the accumulation of amyloid β peptide (Aβ) andhyperphosphorylated tau protein. For 30, the amyloid hypothesis has dominated. However, recently themetabolic and mitochondrial have been considered. Impaired of mitochondrial function is an early eventin the brain aging and probably in the pathogenesis of AD. Mitochondrial dysfunction may affect theexpression and processing of amyloid precursor protein (APP) as well as Aβ accumulation, and thus maybe considered a trigger responsible for the development of molecular and functional changescharacteristic for AD. Therefore, the aim of this study was to investigate the transcription of genesencoding antioxidant proteins, proteins of electron transport chain (ETC) respiratory complexes andproteins regulating mitochondrial fusion/fission and biogenesis in a cellular model of Aβ42 oligomers(AβO) cytotoxicity and in an animal model of AD. Moreover, the level of selected proteins and theactivity of the final enzyme in the ETC, cytochrome C oxidase were also analyzed. The experiments werecarried out using rat pheochromocytoma (PC12) cells, human neuronal cells (SH-SY5Y) andimmortalized mouse microglial cells (BV2). In addition, the research was carried out on the cerebralcortex obtained from transgenic Tg AD mice 3, 6 and 12 month- old with London mutation (V717I).The results obtained in this dissertation showed that AβO peptides evoke several changes intranscription of genes related to mitochondria and the effect of Aβ oligomers depend on the duration oftheir action and the type of cells. Aβ peptides significantly affected cells viability, the level of freeradicals, with one exception of BV2 microglia cells and activated NAD dependent enzyme Poly (ADPribose) polymerase PARP1. This enzyme and the NAD dependent histone deacetylases type III, Sirtuins,particularly Sirt1 are crucial molecular regulators of cells survival and death.The results demonstrated that PARP-1 inhibitor, by activating gene expression of antioxidantenzymes and proteins of mitochondrial dynamics and subunits of respiratory complexes in a short time ofaction, might positively affect the level of free radicals and the energy state of cells exertingcytoprotective effect. Moreover, the data indicated increase in the level of mRNA for Sod2 in microglialcells subjected to Aβ peptides toxicity. These changes may protect these cells against the activation of thefree radical cascade and may significantly affect their functions. Alteration of transcription of genesencoding antioxidant defense proteins, including SOD2 in mitochondria and NAD-dependent enzymes:SIRT1 and PARP-1, both of nuclear enzyme and recipients of the free radical cascade), were found in thecerebral cortex of AD Tg mice. These changes may impair the function of numerous transcription factorsand the metabolism of APP towards the amyloidogenic pathway.The obtained results indicate that changes in the transcription of genes encoding proteinsof mitochondrial dynamics and biogenesis in the cerebral cortex of AD animals are molecularphenomena, which could be responsible for the progression of pathological processes observed in thisstudy in the early advance stage AD mice (12month- old AD mice). At this time, the most genes engagedin neuroprotective processes are not activated with one exception the enhanced level of mRNA for thesubunit of complex IV. The early stage of AD creates opportunities for the activation of antioxidantenzymes and cytoprotective pathways that can protect cells from processes leading to neurodegenerationand death. Based on the analysis of gene transcription in a mouse model of AD, it can be concluded thatPARP-1 and Fis1 inhibitors and or SIRT1, PPAR s/PGC-1α and NRF2 activators may be promising inneuroprotective strategy in the early stage of AD.

Detailed Resource Type:

PhD Dissertations

Format:

pdf

Resource Identifier:

oai:rcin.org.pl:237325

Source:

IMDiK PAN, sygn. ZS416 ; click here to follow the link

Language:

pol

Rights:

Creative Commons Attribution BY 4.0 license

Terms of use:

Copyright-protected material. [CC BY 4.0] May be used within the scope specified in Creative Commons Attribution BY 4.0 license, full text available at: ; -

Digitizing institution:

Mossakowski Medical Research Institute PAS

Original in:

Library of the Mossakowski Medical Research Institute PAS

Projects co-financed by:

Operational Program Digital Poland, 2014-2020, Measure 2.3: Digital accessibility and usefulness of public sector information; funds from the European Regional Development Fund and national co-financing from the state budget.

Access:

Open