Pathological calcium influx through amyloid beta pores disrupts synaptic function

Abstract

Alzheimer's disease (AD) is characterized by profound disruption of synaptic function, with mounting evidence suggesting that amyloid-β (Aβ) oligomers disrupt calcium (Ca²⁺) homeostasis through membrane pore formation. While these pores are known to alter intracellular Ca²⁺ dynamics, their immediate impact on synaptic transmission and potential interaction with Familial AD (FAD)-associated endoplasmic reticulum (ER) dysfunction remains unclear. Here, we extend our previously developed model of presynaptic Ca²⁺ dynamics to examine how Aβ pores alter exocytosis and how such disruptions may manifest in the presence of FAD-associated ER dysfunction. Our model reveals that Aβ pores fundamentally alter both the timing and strength of neurotransmitter release. Unexpectedly, the impact of pores on synaptic function depends critically on their pattern of activity, where continuous pore activity leads to synaptic hyperactivation, while brief periods of intense pore activity trigger lasting hypoactivation at short timescales. These effects manifest most strongly in synapses with low and intermediate release probabilities, highlighting the established selective vulnerability of such synaptic configurations. We find that Aβ pores and FAD-driven ER Ca²⁺ dysregulation form an integrated pathological unit through bidirectional coupling of their respective Ca²⁺ microdomains to create complex patterns of disruptions. This coupling creates a feedback loop that produces an additive effect on neurotransmitter release during brief stimulations, but non-additive effects during sustained activity that promotes a shift towards asynchronous release. Surprisingly, our simulations predict that extended pore activity does not worsen indefinitely but only produces a modest additional disruption beyond initial pore formation that is likely determined by the intrinsic properties of the synapse. These findings indicate that early synaptic dysfunction in AD may arise from subtle perturbations in the temporal coordination of release rather than gross Ca²⁺ dysregulation, providing new mechanistic insights into the progressive nature of Aβ-driven synaptic failure in AD.