Gildenberg Award: Exploring Amyloid β-Induced Neurodegeneration in a Novel Ex Vivo Human Brain Slice Model: Insights into Pathology and Therapeutic Potentials

Introduction: Amyloid β protein(Aβ) is the primary component of neuritic plaques in Alzheimer’s disease(AD) and is widely regarded as the key molecular driver behind the development and progression of the disease. However, the exact pathophysiological effect of Aβ on the brain cells remains poorly understood, mainly due to the lack of replicate disease models, which limit the temporal observation and analysis of the disease. In this study, we use a novel ex-vivo human brain slice model along with Aβ seeding with the aim of studying the disease pathological processing and investigate therapeutic effects.

Methods: Brain specimens were collected from patients undergoing surgery for epileptogenic disconnection, and slices were prepared following a novel protocol. This process included initial oxygenation in artificial-CSF, followed by culture in neuroprotective media. The brain slices were then treated with a proprietary Aβ polymer for 48hours. Calcium imaging with FLUO-4AM was used to assess changes in calcium dynamics within the slices and neuronal firing. RNA was subsequently extracted and analyzed via Next-Generation-Sequencing. Lastly, the therapeutic potential of Baricitinib was evaluated.

Results: Following treatment with Aβ polymer, calcium imaging demonstrated significant alterations in calcium dynamics and decreased neuronal firing within treated slices compared to controls(P < 0.001). Transcriptomic analysis of brain slices revealed a differential expression of key genes involved in neuroinflammation, synaptic plasticity, and calcium regulation, reflecting potential molecular responses to Aβ treatment. Baricitinib treatment mitigated the abnormal calcium dynamics, restoring the neural firing rate to levels similar to those of control slices(P>0.05). Additionally, transcriptomic data indicated reversibility of >50% of the DEGs induced by Aβ seeding, suggesting Baricitinib’s potential to counteract Aβ-related molecular alterations.

Conclusion : This study presents a novel model for the temporal investigation of AD, and the findings suggest that Baricitinib may effectively counteract Aβ-induced neural dysfunction, highlighting its potential as a therapeutic agent for modulating neuroinflammatory and neurodegenerative processes.