University of Sussex
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Aß’s effect on long term memory: a top-down approach in Lymnaea stagnalis

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posted on 2023-06-08, 22:12 authored by Lenzie Katherine Ford
Amyloid ß(Aß)-induced synaptic and neuronal degeneration has been linked to the memory loss observed in Alzheimer’s disease (AD). Although Aß-induced impairment of synaptic and nonsynaptic plasticity is known to occur before any cell death, the links between these neurophysiological changes and the loss of specific types of behavioural memory are not fully understood. This thesis introduces a behaviourally and physiologically tractable animal model to the Aß field for the first time, allowing for an in-depth approach to investigating Aß-induced memory loss to be explored. In Aß 1-42- and Aß 25-35-treated Lymnaea stagnalis, retrieval of consolidated memory is disrupted after single-trial conditioning and single-injection of synthetic peptide. All succeeding work builds upon these findings using a top-down approach to investigate how Aß disrupts retrieval of consolidated memory. Neuronal and synaptic health were monitored over a 24 hour in vivo incubation period and other memory stages were considered to determine time points of memory vulnerability. In brains that displayed healthy neurons and degenerating synapses, only animals that were exposed to Aß during the 24-48 hour post-training time points exhibited any behavioural deficits. All other behavioural responses remained normal. Focus then shifted to investigate the peptide, as opposed to behaviour, involved in the above mentioned experiments. After systemic injection, Aß was found to penetrate the ganglia, enter cells, and localise to specific organelles by 24 hours exposure. Aß morphology and structure were also monitored over the 24 hour incubation period, using transmission electron microscopy (TEM), formic acid extraction, silver stain, and western blot. A large distinction between the two peptides, Aß 1-42 and Aß 25-35, became apparent at this point and even when peptides were prepared using the same procedure, their effects on behaviour became drastically different. However, it is interesting to note that although the two peptides used are very different, under different preparation procedures they will both produce predominantly tetramer species after 24 hour in vivo incubation. Finally, investigations into disruptions of molecular signalling cascades were considered in order to correlate these disruptions to the observed Aß-induced behavioural deficits. Specifically, molecular, pharmacological, and biochemical techniques were used to measure protein alterations and post-translational modifications, and to inhibit key protein components, involved in cAMP response element binding protein (CREB)-signalling pathways in Lymnaea brain after 24 hour in vivo incubation of Aß. Phosphorylated CREB was found to be decreased in both Aß-treated groups; this decrease pattern was also found in active protein kinase A (PKA) experiments. These experiments correlate memory deficits to Aß-induced disruptions in PKA and CREB activity; however, PKA inhibition experiments indicate that this molecular cascade disruption is not sufficient to cause the observed behavioural deficits. Taken together, this work correlates Aß-induced changes from a wide range of components involved in learning and memory, with Aß-disrupted memory recall. Importantly as well, this work develops Lymnaea stagnalis as a novel model for Aß research and continues to distinguish the two commonly used peptides, Aß 1-42 and Aß 25-35. By linking the effects of Aß on defined neuronal circuits to behavioural deficits in a novel model, the Aß field has been further developed in an important and unique way.


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