INVESTIGATING THE ROLE OF AMYLOID-Β ON NEUROPHYSIOLOGICAL FUNCTION ACROSS BRAIN REGIONS

In Alzheimer’s disease abnormal accumulation and aggregation of amyloid beta (Aβ) is a key pathological hallmark, and is associated with neuronal hyperactivity in model systems. Aβ pathology has a stereotypical pattern, defined in thal stages, beginning in the neocortex progressing with disease progression, with the final phases involving brainstem and cerebellar Aβ-deposits. This suggests distinct brain regions may be more susceptible to pathological accumulation than others. However, whether different brain regions have different functional susceptibilities in response to Aβ alterations is unclear.
Using organotypic brain slice cultures from C57Bl6/j mice from five brain regions, (hippocampus, cerebellum, and three cortical subregions) this work aims to assess how different brain regions respond to increased neuronal activity with or without Aβ alterations, through application of a BACE1 inhibitor or Phosphoramidon. ELISAs will be used to quantify levels of mouse Aβ at baseline, following activity-promoting conditions, and subsequent Aβ manipulations to assess activity-dependent Aβ release. MEA electrophysiological recordings will be used to characterise the functional impact of these perturbations.
Preliminary results suggest differential responses in function and Aβ release in response to Aβ-related disruptions within cerebellar cultures, compared to hippocampal and cortical cultures. To enhance translational relevance of the findings, we will compare the responses of the mouse brain slice cultures to live human brain slice cultures exposed to similar Aβ alterations.
This work can help identify regional differences in functional vulnerability to Aβ pathology, informing the development of brain region-specific therapeutic interventions.