CBBS Best Paper of The Year 2022

CBBS spokesperson Prof. Dr. Daniela Dieterich, Prof. Dr. med. Stefan Remy und Prof. Dr. med. Emrah Düzel present the certificates and cheques to the award winners, Fotos: Ritter/LIN

Transversal functional connectivity and scene-specific processing in the human entorhinal-hippocampal circuitry

A group of closely interconnected regions lies deep inside the human brain: The entorhinal-hippocampal circuitry. This circuitry plays a key role when we piece information together in our memory to remember previous experiences. Hence, the entorhinal-hippocampal circuitry is viewed as the „memory machine” of the brain. It is still unknown, though, how exactly this circuitry is able to reconstruct previous experiences in the brain. A major challenge is the size of the entorhinal-hippocampal regions: being not much bigger than a finger altogether, it remains difficult to visualize the activity of single regions within the circuitry in humans. We tackled this challenge with a combination of ultrahigh-resolution neuroimaging and state-of-the-art analysis methods. Thereby we could unravel the fundamental infrastructure of memory in the human brain with unprecedented extent and precision. For the first time, we showed that contextual information of experiences is processed along a highly specified route within the entorhinal-hippocampal circuitry. In a second, partially parallel route, we show however that information from experiences might be integrated earlier than previously thought. These results translated novel findings from animal research to the human brain, now they can be used for further scientific and clinical applications.

Our fundamental results are particularly interesting because Alzheimer’s disease pathology starts accumulating specifically in one of our identified routes. Our basic science thus might have direct clinical implications via the development and optimization of diagnostic tests that target information specifically in that route and which can hopefully detect Alzheimer’s disease earlier than before.

Our findings are particularly interesting because Alzheimer's disease specifically begins to accumulate in one of the routes we have identified. This means that our basic research has direct clinical relevance. On the one hand, through mechanistic follow-up studies to investigate the extent to which Alzheimer's pathology spreads along the entorhinal-hippocampal circuit. On the other hand, through the development and optimization of diagnostic tests that target information specifically in that route and that hopefully allow to detect and track Alzheimer's disease earlier than before.

Jacob-induced transcriptional inactivation of CREB promotes Aß-induced synapse loss in Alzheimer’s disease

Synaptic malfunctions caused by the amyloid-β peptide are characteristic of the initial stage of Alzheimer's dementia (AD) and are directly associated with early cognitive impairment.

Little attention has been paid to the fact that amyloid-β inactivates the transcription factor CREB via as yet unknown mechanisms. Transcription factor CREB is of the greatest relevance for the expression of genes that ensure the so-called synaptic plasticity and thus cognitive abilities. Consequently, the inactivation of CREB, commonly denoted as CREB shutoff, is concomitant with a substantial impairment in synaptic function.

How to protect CREB from inactivation to improve cognitive flexibily in the context of AD?

Dr. Anna Karpova and Dr. Michael R. Kreutz, together with colleagues from Hamburg, Münster, and Magdeburg, investigated the role of transcriptional inactivation of CREB (so-called CREB shutoff) in the impairment of hippocampal synapses in an established mouse model for AD. They demonstrated that the intracellular transport of a multiprotein complex to the cell nucleus - starting from NMDA receptors, which are known for their key role in synaptic plasticity as well as in neurodegeneration - induces the CREB shutoff.

The Jacob protein, a synapto-nuclear messenger protein, activates or inactivates CREB depending on the physiological status of the synapses and the molecular identity of the signalosome. In the brain of AD patients, amyloid-β affects the composition of the signalosome in such a way that CREB is inactivated by displacement of its co-activator LMO4 by Jacob. This finding led the research team to an in silico screen in which, among 100,000 chemical compounds, the relatively small molecule Nitarsone was identified as a substance with a potentially CREB shutoff-suppressing effect. In fact, it has been experimentally confirmed that Nitarsone blocks the formation of the signalosome responsible for the inactivation of CREB (Jacob-LMO4 complex). With regard to possible therapeutic approaches, the data according to which Nitarsone proved to be highly effective in maintaining synaptic plasticity and avoiding cognitive deficits in the mouse model for AD are very encouraging.