Characterization of microglial Rab7 knockout on amyloid pathology in the 5xFAD mouse model of Alzheimer’s disease

Characterization of microglial Rab7 knockout on amyloid pathology in the 5xFAD mouse model of Alzheimer’s disease

Beate Maren Erika Koch

Doctoral thesis

Date of Examination: 2018-11-20

Date of issue: 2019-11-08

Advisor: Schneider, Anja PD Dr.

Referee: Schneider, Anja PD Dr.

Referee: Rizzoli, Silvio Prof. Dr.

Persistent Address: http://hdl.handle.net/21.11130/00-1735-0000-0005-12A0-1

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Abstract

English

Microglia are the innate immune cells of the brain. In neurodegeneration, such as Alzheimer’s disease, these cells are involved in clearance of cellular debris and extracellular aggregates of misfolded proteins like amyloid beta (Aβ). However, alongside Aβ-clearance microglia are activated, resulting amongst others in the secretion of neurotoxic cytokines which contributes to neuronal cell death. Hence, it is not well understood whether microglia are beneficial or detrimental for the progression of AD. To address this question, we generated 5xFAD transgenic AD mice with microglia-specific depletion of Rab7 GTPase (Rab7ΔMG x 5xFAD), which is responsible for the fusion of late endosomes and autophagosomes with the lysosome, and thereby promotes lysosomal degradation. Surprisingly, we found that Rab7ΔMG x 5xFAD mice revealed fewer and smaller Aβ-plaques in aged female mice, while the overall amounts of soluble and insoluble Aβ-species were not changed in early (3 months) and progressed (9 months) stages of disease. We did not observe changes in micro- and astrogliosis. However, elevated levels of CCL2 were detected, which could provide a mechanism to attract peripheral derived myeloid cells which could compensate for degradation impaired Rab7 knockout microglia. All of these findings were exclusively found in female Rab7ΔMG x 5xFAD mice. This could either be caused by higher basal Aβ-burden in females or by sex-dependent differential features of microglia, including phago-lysosomal activity.

Keywords: Microglia; Alzheimer's disease