Der Einfluss der Formyl-Peptid-Rezeptor Modulation auf die Alzheimer Erkrankung

  • The influence of formyl peptide receptor modulation on Alzheimer’s disease

Schröder, Nicole; Brandenburg, Lars-Ove (Thesis advisor); Pradel, Gabriele (Thesis advisor); Fabry, Martha Elisabeth (Thesis advisor)

Aachen : RWTH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021


The Alzheimer’s disease (AD) is one of the best known neurodegenerative diseases. A main hallmark is the accumulation of the extracellular beta amyloid (Aβ) peptides. In addition to the characteristic neurodegeneration, neuroinflammation has become the focus of research in recent years. Therapeutic approaches to influence the inflammatory response require a starting point, which is often found in receptors. One group of these receptors is the family of formyl peptide receptors (FPRs). In order to decipher the exact role of these FPRs in AD, different approaches were used in this study to analyze the development of amyloid beta plaque formation, neuroinflammation and neurodegeneration. Using an AD mouse model (APP/PS1), two with an additional Fpr1 or Fpr2 deficit, these key points were examined. In a second approach, the Fpr2 antagonist WRW4 was administered APP/PS1 mice over a period of 20 weeks. The animals first underwent a Morris water maze (MWM) and were then examined immunohistochemically as well as on molecular biological level. The experiments demonstrated that spatial orientation and memory performance of Alzheimer's mice were additionally impaired by Fpr2 KO as well as Fpr2 inhibition. This could not be determined for Fpr1 KO. A Fpr1 and Fpr2 KO in APP/PS1 seems to reduce neuronal death, whereas Fpr2 inhibition with WRW4 does not induce this positive effect. Furthermore, slightly altered gene expression of neurotrophic factors was detected in Fpr-deficient mice. Alzheimer-induced astrogliosis is partially exacerbated by Fpr KO or inhibition, whereas the characteristic microgliosis tends to be attenuated by Fpr KO. Although the morphology of the cells is still altered, as in AD characteristic, the amount of microglial cells around amyloid plaques is reduced. In addition, gene expression of the anti-inflammatory interleukin 10 (Il-10) is enhanced in Fpr-deficient APP/PS1 mice. Fpr1 KO caused a reduced number of Aβ plaques, whereas a Fpr2 deficit and Fpr2 inhibition only tended to do so. In summary, it is interesting to note that the Fpr1 deficit in particular have a potential positive effect on the progression of AD and could be a suitable starting point for potential therapeutics.