posted on 2012-06-01, 00:00authored byDaniela Hartl, Victoria Schuldt, Stephanie Forler, Claus Zabel, Joachim Klose, Michael Rohe
Glucose hypometabolism is the earliest symptom observed
in the
brains of Alzheimer disease (AD) patients. In a former study, we analyzed
the cortical proteome of the APP23 mouse model of AD at presymptomatic
age (1 month) using a 2-D electrophoresis-based approach. Interestingly,
long before amyloidosis can be observed in APP23 mice, proteins associated
with energy metabolism were predominantly altered in transgenic as
compared to wild-type mice indicating presymptomatic changes in energy
metabolism. In the study presented here, we analyzed whether the observed
changes were associated with oxidative stress and confirmed our previous
findings in primary cortical neurons, which exhibited altered ADP/ATP
levels if transgenic APP was expressed. Reactive oxygen species produced
during energy metabolism have important roles in cell signaling and
homeostasis as they modify proteins. We observed an overall up-regulation
of protein oxidation status as shown by increased protein carbonylation
in the cortex of presymptomatic APP23 mice. Interestingly, many carbonylated
proteins, such as Vilip1 and Syntaxin were associated to synaptic
plasticity. This demonstrates an important link between energy metabolism
and synaptic function, which is altered in AD. In summary, we demonstrate
that changes in cortical energy metabolism and increased protein oxidation
precede the amyloidogenic phenotype in a mouse model for AD. These
changes might contribute to synaptic failure observed in later disease
stages, as synaptic transmission is particularly dependent on energy
metabolism.