Mechanisms of amyloid-beta cytotoxicity in hippocampal network function : rescue strategies in Alzheimer's disease

The origin and nature of cognitive processes are strongly associated with synchronous rhythmic activity in the brain. Gamma oscillations that span the frequency range of 30–80 Hz are particularly important for sensory perception, attention, learning, and memory. These oscillations occur intrinsically in brain regions, such as the hippocampus, that are directly linked to memory and disease. It has been reported that gamma and other rhythms are impaired in brain disorders such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia; however, little is known about how these oscillations are affected.

In the studies contained in this thesis, we investigated a possible involvement of toxic Amyloid-beta (Aβ) peptide associated with Alzheimer’s disease in degradation of gamma oscillations and the underlying cellular mechanisms in rodent hippocampi. We also aimed to prevent possible Aβ-induced effects by using specially designed molecular tools known to reduce toxicity associated with Aβ by interfering with its folding and aggregation steps.

Using electrophysiological techniques to study the local field potentials and cellular properties in the CA3 region of the hippocampus, we found that Aβ in physiological concentrations acutely degrades pharmacologically-induced hippocampal gamma oscillations in vitro in a concentration- and time-dependent manner. The severity of degradation also increased with the amount of fibrillar Aβ present.

We report that the underlying cause of degradation of gamma oscillations is Aβ-induced desynchronization of action potentials in pyramidal neurons and a shift in the equilibrium of excitatory-inhibitory synaptic transmission. Using specially designed molecular tools such as Aβ-binding ligands and molecular chaperones, we provide evidence that Aβ-induced effects on gamma oscillations, cellular firing, and synaptic dynamics can be prevented. We also show unpublished data on Aβ effects on parvalbumin-positive baskets cells or fast-spiking interneurons, in which Aβ causes an increase in firing rate during gamma oscillations. This is similar to what is observed in neighboring pyramidal neurons, suggesting a general mechanism behind the effect of Aβ.

The studies in this thesis provide a correlative link between Aβ-induced effects on excitatory and inhibitory neurons in the hippocampus and extracellular gamma oscillations, and identify the A aggregation state responsible for its toxicity. We demonstrate that strategies aimed at preventing peptide aggregation are able to prevent the toxic effects of Aβ on neurons and gamma oscillations. The studies have the potential to contribute to the design of future therapeutic interventions that are aimed at preserving neuronal oscillations in the brain to achieve cognitive benefits for patients.

List of scientific papers

I. Kurudenkandy FR, Zilberter M, Biverstål H, Presto J, Honcharenko D, Strömberg R, Johansson J, Winblad B and Fisahn A. Amyloid-beta-induced action potential desynchronization and degradation of hippocampal gamma oscillations is prevented by interference with peptide conformation change and aggregation. The Journal of Neuroscience. 2014;34(34):11416-25.
https://doi.org/10.1523/JNEUROSCI.1195-14.2014

II. Honcharenko D, Bose PP, Maity J, Kurudenkandy FR, Juneja A, Floistrup E, Biverstål H, Johansson J, Nilsson L, Fisahn A and Stromberg R. Synthesis and evaluation of antineurotoxicity properties of an amyloid-beta peptide targeting ligand containing a triamino acid. Organic and Biomolecular Chemistry. 2014;12(34):6684-93.
https://doi.org/10.1039/c4ob00959

III. Cohen SI, Arosio P, Presto J, Kurudenkandy FR, Biverstal H, Dolfe L, Dunning C, Yang X, Frohm B, Vendruscolo, Johansson J, Dobson C.M, Fisahn A, Knowles T.P.J and Linse S, A molecular chaperone breaks the catalytic cycle that generates toxic Abeta oligomers. Nature Structural Molecular Biology. 2015;22(3):207-13.
https://doi.org/10.1038/nsmb.2971

IV.Poska H, Haslbeck M, Kurudenkandy FR, Hermansson E, Chen G, Kostallas G, Biverstål H, Crux H, Fisahn A, Presto J and Johansson J. Dementia related Bri2 BRICHOS is a molecular chaperone that efficiently inhibits Aβ42 toxicity in Drosophila. Biochemical Journal. 2016. [Epub ahead of print]
https://doi.org/10.1042/BCJ20160277