Ablation of cell-specific cholesterol synthesis affects cerebral β-amyloidosis

by Lena Spieth
Doctoral thesis
Date of Examination:2022-05-02
Date of issue:2023-03-13
Advisor:Dr. Gesine Saher
Referee:Prof. Dr. Thomas Bayer
Referee:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Rüdiger Behr
Referee:Prof. Dr. Susann Boretius
Referee:Dr. Nico Posnien
Persistent Address: http://dx.doi.org/10.53846/goediss-9780

 

 

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Abstract

English

Cholesterol, an essential membrane component, among others modifies membrane fluidity and regulates cell signaling. CNS cholesterol metabolism is separated from peripheral cholesterol by specific properties of the blood-brain-barrier. Therefore, cholesterol homeostasis within the lipid-rich brain is maintained by ne novo synthesis. In principle, every brain cell is capable of synthesizing cholesterol although astrocytes are generally considered to be the major producers that subsequently release and horizontally transfer cholesterol via lipoproteins to other brain cells. Intriguingly, disturbances in CNS cholesterol metabolism have been linked to Alzheimer´s disease (AD). Major genetic risk factors for sporadic AD are gene variants of apolipoprotein E (ApoE) and the apolipoprotein J (ApoJ). These lipoprotein variants have been considered to not only affect horizontal cholesterol transfer but also seeding, spreading and clearance of senile plaques. Most importantly, the primary neuropathological hallmark, extracellular senile plaques composed of amyloid β-peptides, is influenced by amyloid precursor protein (APP) metabolism which is predominantly situated in cholesterol-rich membrane lipid rafts in neurons. However, how exactly disturbances of CNS cholesterol homeostasis contributes to its pathogenesis is elusive. This study is aimed at elucidating the role of de novo cholesterol synthesis in different cell types in mouse models of AD. The effect on amyloid burden by abolishing cholesterol synthesis in neurons, astrocytes, and microglia, respectively, was analyzed. This was achieved by cell-type specific genetically inactivated cholesterol synthesis gene Fdft1. The Fdft1 gene encodes squalene synthase which catalyzes the first committed step of cholesterol synthesis. Surprisingly, lack of cholesterol synthesis in neurons did not alter APP processing or amyloid plaque burden. In contrast, glial cholesterol synthesis influenced the density of amyloid plaques. Whereas the disturbance of cholesterol in astrocytes resulted in a decrease in amyloid plaques, unexpectedly, mice lacking cholesterol synthesis in microglia showed an extensive increase. Using a transcriptomic approach, it could be shown that microglial cholesterol was required to mount the full DAM (disease associated microglia) signature upon amyloid exposure. In contrast, coverage of amyloid plaques by microglia was surprisingly increased. This work unraveled important cell- and glia-type- specific differences in the role of cholesterol synthesis on plaque metabolism. The here presented data suggest sterol synthesis in glia cells as an important disease modifier with intriguing opposite effects of astrocytic and microglial cholesterol synthesis inactivation. In addition, the findings highlight the need for cell-type specificity in the development of cholesterol-targeting drugs to combat AD.
Keywords: cholesterol; Alzheimer´s disease; amyloid; microglia; cell-specific
 
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