BDNF/TRKB Signaling Pathway Altered by Six Weeks of Exercise in the Aged APOE4
Alzheimer’s Mouse Model
Joseph Maged Seif
Mentor: Carl W. Cotman
ApoE4 is a risk factor gene for Alzheimer’s disease. This study explores potential cellular
mechanisms by which exercise improves the cognitive performance in the ApoE4
targeted replacement mouse model, using the ApoE3 targeted replacement as a control.
After six weeks of ad libitum running, sedentary and run animals (eight E3 sedentary,
eight E3 run, seven E4 sedentary, and eight E4 run) were cognitively tested on single
(place recognition) and multiple-day (radial arm water maze), hippocampus-dependent
memory tasks. The animals were sacrificed and testing and quantification of four
hippocampal proteins—BDNF, TrkB, PAK, and synaptophysin—took place using
ELISA and Western blots. Run mice from both genotypes improved equally on the place
recognition task (single day), while only the exercised ApoE4 mice improved on the
radial arm water maze task (multiple-day). BDNF increased similarly in both genotypes
with running (p<0.05); however, a significant interaction of genotype and condition
existed for TrkB, PAK, and synaptophysin (p<0.05; p<0.01; p<0.01, respectively). Posthoc tests revealed that increases in the levels of the aforementioned proteins were largely
restricted to the ApoE4 genotype. The increased levels of synaptophysin indicate
increased synaptogenesis, which may explain the differential improvement in ApoE4
running mice on cognitive tasks involving multiple days. This may provide hope for
controlling the cognitive deficits of ApoE4 Alzheimer’s carriers, by means of increased
synaptogenesis through exercise intervention.