Contributor:

Czapski, Grzegorz A.

Publisher:

Instytut Medycyny Doswiadczalnej i Klinicznej im. Miroslawa Mossakowskiego PAN

Place of publishing:

Warszawa

Level of degree:

2

Degree discipline :

medical sciences

Type of object:

Thesis

Abstract:

Neurodegenerative diseases represent a major medical challenge due to their increasing prevalence and lack of effective therapies. Chronic neuroinflammation is a key component of their pathogenesis, in which excessive microglial activation leads to neuronal damage, synaptic dysfunction, and accumulation of pathological protein aggregates, including amyloid-β (Aβ) and hyperphosphorylated Tau. The limited efficacy of current anti- inflammatory strategies highlights the need for novel molecular targets, such as BET family proteins that regulate inflammatory gene expression. The aim of this study was to investigate the role of BET proteins in the regulation of microglial function and neuroinflammatory processes. Experiments were conducted using three models: in vitro (BV2 cells in mono- and co-culture with HT22, stimulated with LPS and Aβ), in vivo (C57BL/6J mice, endotoxemia model), and the maternal immune activation (MIA) model. Both pharmacological (JQ1, OTX-015) and genetic (siRNA) inhibition approaches were applied. Analyses included molecular biology, immunochemical, microscopy, cytometric methods, and behavioural tests. A selective increase in BRD4 expression was observed, indicating its central role in regulating pro-inflammatory gene expression, whereas BRD2 and BRD3 contribute to microglial homeostasis. BET inhibition reduced the expression of phagocytosis-related genes (CD33, TREM2), decreased phagocytic activity, and lowered pro-inflammatory cytokine levels (IL-1β, IL-6, TNF-α). It also attenuated microglia-induced neurotoxicity and reduced hippocampal Aβ levels without affecting Tau phosphorylation, while OTX-015 improved memory performance. These findings demonstrate that BET proteins are key regulators of microglial activity and represent promising therapeutic targets for neurodegenerative diseases, including Alzheimer’s disease.

Detailed Resource Type:

PhD Dissertations

Format:

pdf

Resource Identifier:

oai:rcin.org.pl:262352

Source:

IMDiK PAN, sygn. ZS446

Language:

pol

Language of abstract:

eng

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

Access:

Open