Genetic manipulation of CNS cholesterol metabolism and its effects on cerebral β-amyloidosis

by Jan Winchenbach
Doctoral thesis
Date of Examination:2018-04-12
Date of issue:2019-03-07
Advisor:Dr. Gesine Saher
Referee:Dr. Gesine Saher
Referee:Prof. Dr. Thomas A. Bayer
Persistent Address: http://dx.doi.org/10.53846/goediss-7274

 

 

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Abstract

English

Accumulating evidence implicates cholesterol metabolism in the pathogenesis of Alzheimer’s disease (AD). However, the underlying mechanisms are not well understood. In the brain, cholesterol is synthesized locally by different cell types during development and in adulthood. The current understanding is that astrocytes are likely the major producers of cholesterol in the adult brain. However, in vivo evidence has been limited by the lack of genetic tools that allow efficient targeting of gene function in adult astrocytes. In this study, a newly generated BAC transgenic mouse line that expresses tamoxifen inducible Cre recombinase under control of the Aldh1l1 promoter was characterized. Analyses revealed that astrocytes in brain and spinal cord are targeted with high efficiency. Using this mouse line we inactivated cholesterol synthesis in adult astrocytes by targeting of squalene synthase (SQS), the enzyme catalyzing the first committed step in cholesterol biosynthesis. Conditional mutants did not show signs of brain pathology and mutant astrocytes were viable. Interestingly, albeit successful inactivation of SQS in astrocytes, brain cholesterol homeostasis was largely unaltered, suggesting compensatory efforts by other cell types. To address the role of astrocytic cholesterol synthesis in cerebral β-amyloidosis, we crossed conditional mutants with 5xFAD mice, an animal model of AD. In the hippocampus of these compound mutants, we found reduced deposition of Aβ42 peptides accompanied by increased expression of Trem2 (triggering receptor expressed on myeloid cells 2). Although further investigation is required, Trem2 could potentially facilitate Aβ clearance by microglia cells in these mutants. Together, this study indicates that astrocytic cholesterol synthesis is not required in adult mice and underlines the importance of cholesterol metabolism in modulating cerebral β-amyloidosis.
Keywords: Alzheimer's disease; Cholesterol
 
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