Soluble amyloid-β and early hippocampal hyperactivity: implications for understanding Alzheimer's disease

A recent study by Marc Aurel Busche et al. from the Institut für Neurowissenschaften, Technische Universität München in Munich, Germany has revealed the role of soluble amlyloid- β (Aβ) in neuronal hyperactivity, which is linked to early symptoms of Alzheimer's Disease (AD). The onset of AD had been previously linked to the presence of hypoactive neurons in the brain, also known as neuronal silencing, but recent studies have added to this understanding by showing that hyperactive neurons play a similar role in the disease's development. Hyperactive neurons also appear to be most prominent in the vicinity of plaques. It is unclear what comes first, neuronal silencing or hyperactivity, and the role that plaque formation plays in this process. This formed the basis for the study. Busche and his colleagues chose to look at the hippocampal region of the brain because early symptoms of AD like learning and memory loss are known to be the result of hippocampal dysfunction and also because this dysfunction can occur at very early stages of the disease's development, well before the formation of plaques. This region of the brain had not been previously studied because it has been inaccessible to cellular imaging. The use of new methods, specifically the suction removal of the overlying cortex, as well as tools like the fluorescent Ca²⁺ indicator Fluo-8 AM have allowed this part of the brain to be studied to get a better understanding of the relationship between neuronal hyperactivity and hippocampal dysfunction.

The results of the study have profound implications for the pathogenesis of AD and also offer some novel pharmacological treatments that could be directed at altered neurons to help alleviate the symptoms and onset of AD. Essentially, it was found that the formation of an excess of hyperactive neurons develops independently from plaque formation and precedes the neuronal silencing (hypoactivity). The researchers indicated this could be possible because of varying levels of soluble Aβ, which provides evidence for a causal link between the action of soluble Aβ and hyperactivity. The second key finding of the study was that the introduction of y-secretase, which has been shown to reduce soluble Aβ, can help quiet neuronal hyperactivity, which could help to inhibit the learning and memory loss usually experienced in the beginning stages of AD. This provides a new treatment method that is directly linked to the advanced understanding of neuronal activity generated by this study.

Part of what made this study possible was the tools used to conduct it. As mentioned earlier, the suction removal of the overlying cortex method allowed researchers to access the previously untouchable hippocampus. Also, by using Fluo-8^® AM, researchers were able to visibly map the spontaneous activity of neuronal populations in the parts of the brain under study. Fluo-8 AM is a novel fluorescent green calcium indicator marked by enhanced intensity, better and easier loading, and an ability to deliver more robust results. It is helping researchers come to findings like those in this study that promise to make profound advances in the understanding and treatment of major diseases like AD.

References

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1. Busche, M. a., X. Chen, H. a. Henning, J. Reichwald, M. Staufenbiel, B. Sakmann, and a. Konnerth. 2012. "Critical Role of Soluble Amyloid- for Early Hippocampal Hyperactivity in a Mouse Model of Alzheimer's Disease."Proceedings of the National Academy of Sciences 109 (22): 8740–45. doi:10.1073/pnas.1206171109.