AMYLOID-Β OLIGOMER BINDING TRIGGERS TAU HYPERPHOSPHORYLATION AND MICROGLIAL ACTIVATION IN ADULT HUMAN BRAIN SLICE

Soluble oligomers of the amyloid beta peptide (AβOs) are considered the primary agents driving neurotoxicity in the early stages of Alzheimer's disease (AD). Although significant progress has been made in elucidating the molecular mechanisms underlying AβO-induced damage, effective diagnostic tools and disease-modifying therapies remain limited. In this context, human brain slice cultures are attractive and unique as these allow modelling of the mature central nervous system with cellular connectivity and diversity preserved. Consequently, studies on neurotoxic events triggered by proteinopathies, particularly amyloid-β aggregates, using human brain slice cultures as an experimental model, are more likely to reflect biologically relevant phenomena. This study investigates molecular responses elicited by AβOs relevant to early AD pathology, prior to plaque formation, using adult human brain slice cultures. Brain tissue is obtained from adult donors undergoing temporal lobectomy for treatment of refractory epilepsy (Ethics Committee #81445624.1.0000.5440). Briefly, 200µm slices are maintained in free-floating culture and challenged with in vitro-prepared AβOs at day in vitro 2-4. Imaging and functional analyses revealed selective, cell-associated AβO binding, followed by microglial recruitment and astrocytic reactivity. Confocal microscopy further demonstrated Tau hyperphosphorylation in response to AβO exposure. In addition, the release of pro-inflammatory cytokines into the culture medium was assessed. Overall, the data indicate that exogenously applied AβOs trigger a cascade of toxic events in human brain slices that closely mirrors key pathological features observed in AD patients, including Tau abnormalities and neuroinflammatory responses, in the absence of overt cell death.