Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by memory
impairments and dementia. This complex disease includes a long asymptomatic phase. In addition to
amyloid beta and TAU pathologies, AD is linked to early defects in brain energy metabolism and redox
homeostasis. Over the past decade, our laboratory has conducted an extensive study of the interplay
between brain energy metabolism and memory, utilizing Drosophila as a model organism. In view of these
findings, we have recently undertaken research into the potential links between brain energy metabolism
and AD molecular and cellular dysfunctions.
Astrocytes interact with neurons during cognitive processes. Especially, astrocytes help neurons fight
oxidative stress, a needed function since active neurons are prone to reactive oxygen species (ROS)
damage. ROS also play major physiological functions, but it remains unknown how neuronal ROS signaling
is activated during memory formation and if astrocytes play a role in that process. We discovered an
astrocyte-to-neuron H2O2 signaling (ANHOS) cascade essential for long-term memory formation. This
mechanism, revealed by in vivo H2O2 imaging using an ultrasensitive sensor, involves the local synthesis
of beneficial ROS by astrocytic enzymes. Notably, Amyloid Precursor Protein plays a central role in the
ANHOS cascade via its extracellular Cu2+-binding E2 domain. Conversely, Aß hinders ANHOS by
interacting with a major molecular target, the alpha-7 acetylcholine receptor, expressed in astrocytes. Lastly,
I will present preliminary findings suggesting that the expression in astrocytes of APOE4, the major genetic
risk factor in AD, also impairs ANHOS.
Our discovery unveils a novel mechanism of neuronal plasticity essential for long-term memory formation.
It opens the intriguing possibility that, in humans, AD synaptic defects may be initially linked to a deficiency
of beneficial ROS crucial for memory formation, with the observed oxidative stress in AD being a secondary
effect.
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