Upregulated Ca2+ Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer’s Disease

Abstract

Neurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca2+ influx through membrane-resident voltage-gated Ca2+ channels (VGCCs). Moreover, accumulating evidence indicates that the endoplasmic reticulum (ER) is extensively present in axonal terminals of neurons and plays a modulatory role in synaptic transmission by regulating Ca2+ levels. Familial Alzheimer’s disease (FAD) is marked by enhanced Ca2+ release from the ER and downregulation of Ca2+ buffering proteins. However, the precise consequence of impaired Ca2+ signaling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in silico experiments of intracellular Ca2+ signaling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca2+ signaling on neurotransmitter release in FAD. Our model predicts that enhanced Ca2+ release from the ER increases the probability of neurotransmitter release in FAD. Moreover, over very short timescales (30–60 ms), the model exhibits activity-dependent and enhanced short-term plasticity in FAD, indicating neuronal hyperactivity—a hallmark of the disease. Similar to previous observations in AD animal models, our model reveals that during prolonged stimulation (~450 ms), pathological Ca2+ signaling increases depression and desynchronization with stimulus, causing affected synapses to operate unreliably. Overall, our work provides direct evidence in support of a crucial role played by altered Ca2+ homeostasis mediated by intracellular stores in FAD.

Intracellular Injection of Brain Extracts from Alzheimer’s Disease Patients Triggers Unregulated Ca2+ Release from Intracellular Stores That Hinders Cellular Bioenergetics

“…Moreover, over very short timescales (30–60 ms), the model exhibits activity-dependent and enhanced short-term plasticity in AD, indicating neuronal hyperactivity. Similar to previous observations in AD animal models, pathological Ca 2+ signaling increases depression and stimulus desynchronization causing affected synapses to operate unreliably [ 44 ].…”

“…In line with this interpretation are the results from our recent study using a biophysical model of hippocampal synapses to investigate the effect of aberrant Ca 2+ signaling on neurotransmitter release [ 44 ]. The model predicts that enhanced Ca 2+ release from the ER increases the probability of neurotransmitter release in AD-affected neurons.…”

Mechanisms of Cadmium Neurotoxicity

“…The release of a neurotransmitter occurs within hundreds of milliseconds following the action potential to ensure precise communication between neurons [28]. Indeed, several studies have linked asynchronous release to neurodegenerative disease pathologies in AD, spinal muscular atrophy (SMA), and ALS [67][68][69][70]. Cadmium may augment asynchronous neurotransmitter release, further aggravating these neurodegenerative disease pathologies.…”

Association between the Composition of Drinking Water and Cognitive Function in the Elderly: A Systematic Review

“…Calcium has been found to have a protective role in AD development, while oversupplementation of calcium has also been shown to increase the risk of AD. Extracellular accumulation of amyloid plaques and intracellular neurofibrillary tangles in the brain is present in AD, and calcium dysregulation has been shown to induce synaptic deficits and promote the accumulation of the plaques and neurofibrillary tangles [ 32 , 33 , 34 , 35 ].…”