The role of STAT1 signal transduction in the pathogenesis of Alzheimer’s disease
by Dr. Luca Büschgens
Date of Examination:2025-06-25
Date of issue:2025-11-06
Advisor:Prof. Dr. Oliver Wirths
Referee:Prof. Dr. Christine Stadelmann-Nessler
Referee:Prof. Dr. Thomas Meyer
Referee:Prof. Dr. Dörthe Katschinski
Referee:Prof. Dr. Ralf Heinrich
Referee:Dr. Wiebke Möbius
Persistent Address:
http://dx.doi.org/10.53846/goediss-11613
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Abstract
English
Chronic neuroinflammation is considered a key hallmark of Alzheimer’s disease (AD) and may represent a central mechanism in its pathogenesis. Microglia, the resident immune cells of the central nervous system (CNS), are crucial mediators in this complex and dysregulated process. Under physiological conditions, microglia contribute to neural homeostasis through functions such as synaptic pruning and surveillance. In response to CNS injury or infection, they constitute the first line of immune defense by initiating inflammatory responses, producing reactive oxygen species (ROS), and performing phagocytosis of pathogens and cellular debris. However, when chronically dysregulated - as observed in AD - microglial activity can exert significant harm on the neuronal environment, primarily through continuously activated cytotoxic mechanisms. To selectively alter microglial activation pathways and thereby investigate the impact of microglial modulation rather than complete deletion or suppression, we generated AD mouse models with impaired interferon-α and-γ (IFN) signaling. This was achieved by selectively disrupting STAT1 signal transduction. Specifically, we crossed the established 5xFAD transgenic model with either STAT1-/- mice, which are devoid of both IFN-α and-γ signaling, or STAT1-F77Aki/ki mice, which exhibit dysfunctional STAT1 signaling and consequently lack IFN-γ signaling alone. As a third model, we generated the Tg4-42/STAT1-/- line by crossing the Tg4-42 AD model, characterized by intraneuronal Aβ4-42 accumulation and CA1 region specific neuronal loss in the absence of extracellular plaques, with the STAT1-/- line. We questioned whether selective inhibition of IFN signaling would impact the progression of AD pathologies including amyloid-β accumulation, neuroinflammation and cognitive deficits. Additionally, we sought to explore how specific microglial functions - such as phagocytosis, plaque compaction, and cytotoxic actions towards surrounding neuronal tissue - would be affected by the absence of functional IFN signaling in the context of amyloid pathology. Counterintuitively, microglial activation was not suppressed or even reduced, but rather elevated, particularly in response to the combined deficiency in IFN-α and IFN-γ sig naling in the newly generated 5xFAD/STAT1-/- mouse line. Employing bulk transcriptome analysis, RT-qPCR, and immunohistochemical techniques, we demonstrated that 5xFAD/STAT1-/- mice displayed an earlier and more pronounced microglial response. This was characterized by increased expression of disease-associated microglia (DAM) signature genes, increased plaque coverage, and elevated Aβ peptide internalization. While the overall plaque burden, as assessed by 3D light-sheet microscopy, was significantly reduced, total Aβ concentration levels in the SDS-soluble fraction, measured by electrochemiluminescence assays, remained unchanged. We further demonstrated at the immunohistochemical level that this overt discrepancy was likely due to enhanced microglia-mediated plaque compaction in the 5xFAD/STAT1-/- mice. The significantly increased plaque compaction was accompanied by reduced axonal dystrophy around the dense-core plaques. Consistent with the reduced axonal damage, we also observed a complete rescue of spatial memory deficits, assessed by the novel object location paradigm. Although the effects on microglia were less pronounced and partially different in the 5xFAD/STAT1-F77Aki/ki line, a similar neuropathological pattern was observed, with reduced extracellular plaque burden despite unchanged Aβ concentration levels. This was again accompanied by increased plaque compaction, reduced axonal dystrophy and a restoration of spatial memory function. Our findings underscore the central and crucial role of microglia in the progression of AD-related pathologies. By appropriately performing functions such as scavenging and internalizing Aβ peptides, followed by remodeling and compaction of extracellular plaques, microglia might play a decisive role in mediating whether amyloid accumulation translates into neurotoxic effects and progresses towards exacerbated neuropathology. We therefore identify their delicately regulated activation, which enables them to adopt a range of functions and dynamically interchangeable phenotypic states, as a potentially critical regulatory node for therapeutic intervention and a deeper un derstanding of the disease mechanisms in AD.
Keywords: Alzheimer's disease; Microglia; Neuroinflammation; DAM; 5xFAD; Interferon; STAT1; Neurodegeneration; Phagocytosis; Amyloid-β
