Amyloid-beta fibrils as active contributors to synaptic dysfunction in Alzheimer's disease

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by the accumulation of amyloid-beta (Aβ) aggregates, in the form of fibrils and plaques. While it has largely been stated that Aβ oligomers are the main toxic species, significant evidence indicates that fibrils may also be relevant to AD pathogenesis. Notably, evidence indicates that while fibrils, through direct interaction with neuronal membranes, contribute to synaptic dysfunction and cellular damage, no direct evidence between fibrils and their impact on neuronal functions, including plasticity, was investigated. This study inquired into the impact of Aβ fibrils complex on neuronal function and membrane integrity, shedding light on their contribution to synaptic defects. Aβ fibrils were generated from Aβ1-42 oligomers, and their effects were evaluated on synaptic plasticity in ex vivo hippocampal slices from both female and male mice. Compared to Aβ1-42 oligomers, fibrils induced more severe damage in synaptic plasticity, emphasizing their potent neurotoxicity effect underlying cognitive decline. Additionally, using a liposomal model to examine fibril-membrane interactions, it was observed that Aβ fibrils are able to affect membrane fluidity compared to the Aβ1-42 oligomeric species, indicating that the size and aggregation state of Aβ fibrils are crucial for their toxicity. These findings challenge the view that oligomers are the primary toxic species in AD, showing that Aβ fibrils also play an active role in cellular dysfunction, promoting a synaptic dysfunction correlated to the cognitive impairment observed in AD.