gms | German Medical Science

Question: Alzheimer's disease (AD) is characterized by cerebral beta-Amyloid (Abeta) deposits, progressive loss of cognitive performance and by behavioral and psychiatric symptoms like increased anxiety. The Ephrin cascade regulates hippocampal (HC) synaptic plasticity and amygdala triggered anxiety. In AD mouse models, impaired HC Ephrin signaling precedes cognitive decline, whereas reversing Ephrin depletion rescues cognitive performance. We and others have previously shown that cognitive and physical stimulation antagonizes Abeta pathology, improves cognitive functions and decreases anxiety-related behavior. In the present study we questioned whether these beneficial effects of physical activity go along with modulation of the Ephrin cascade in AD mice.

Methods: Transgenic CRND8 (TG) and wild type (WT) mice were kept in standard housing or in cages supplemented with running wheels for five months, starting from P30. Afterwards, the impact of exercise on Abeta plaque pathology was recorded by immunohistochemistry (IH). Furthermore, in TG and WT mice, Ephrin ligands EFNB2, Efna1 and Efnb3, Ephrin receptors EPHB2, Epha1, Epha2 and Epha4, and Ephrin signaling members and effectors FKBP51 and KLK8 were quantified in AD-vulnerable brain regions HC, entorhinal cortex (EC), and frontal cortex (FC) as well as in amygdala and cerebellum via Western blotting, real-time PCR, or IH.

Results: TG mice showed abnormal levels of EFNB2, EPHB2, FKBP51, Efna1, Efnb3, Epha1 or Epha2 in HC, EC, FC or cerebellum when compared to WTs. Physical activity not only reduced Abeta plaque burden in TG mice but also increased HC EFNB2 and EPHB2 protein levels and lowered AD-related KLK8 over-expression to WT level in the HC and amygdala.

Conclusions: Here we show for the first time that exercise reverses AD-related hippocampal Ephrin depletion and hippocampal and amygdalar KLK8 overabundance, thereby possibly normalizing hippocampus triggered cognitive performance and amygdala controlled anxiety.