The network that binds all neurons together ("neuronal network") is very important for a healthy functioning brain. In Alzheimers disease (AD), there is a disruption in this neuronal network, and it falls out of balance. This disruption in the neuronal network can be observed on different levels in the brain, such as on a synaptic level, circuitry level, within the neuronal network itself, and in memory formation. Within this pillar, these levels are the focus, especially from an AD point of view. More importantly, we do not only want to look at these levels separately, but also how they correlate with each other. A disruption in the neuronal network can have negative effects on what we call a "memory engram". This is a group of neurons that is activated altogether in the formation and retrieval of a specific memory; each memory has a different group of neurons that is activated, so each memory carries its own engram.
As AD is characterized by the amyloid plaques that sit around the neurons, it is crucial that these amyloid proteins are cleared out from the environment in order to maintain a healty neuronal network. Once the plaques are getting too abundant, they will disturb the network, and this can eventually have negative effects on our beloved memory.
In Pillar 2, these concepts are investigated in mouse models of AD. Firstly, we will look into the molecular and cellular factors that determine AD in different cell types and different synapse types. Next, we can examine the effect of pharmacological interventions on the functionality of the neuronal network and the effects on cognition in mouse models. Alongside this research, we will investigate the role of microglia in the synapse, circuitry, and neuronal network, but also the role of early-life stress and nutrition in these models. At last, we will attempt to apply all of this knowledge and all these concepts in a human model. Here, we will make use of so-called "induced pluripotent stem cells", or iPSCs in short, which are derived from the upper layer of our skin. We can then completely reprogram these cells, and make them grow in any shape of direction we want; in this case, we will guide them to becoming neurons. These models are complex, yet powerful, as we can test for the same molecular and cellular mechanisms that we may have found in the animal models.
Pillar 2 is led by prof. Paul Lucassen (UvA) and prof. Ronald van Kesteren
(VU), as they work together with Harm Krugers (UvA), Aniko Korosi (UvA), Helmut Kessels (UvA), en Priyanka Rao Ruiz (VU). They will all supervise PhD students, postdocs, and other (non-)scientific staff.
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