Editors' ChoiceNeurodegeneration

New connections: Amyloid-β, calcium, and the synapse

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Science Signaling  11 Jul 2017:
Vol. 10, Issue 487, eaao3024
DOI: 10.1126/scisignal.aao3024

Insight into how amyloid-β impairs synaptic function reveals potential therapeutic targets for patients with Alzheimer’s disease.

Alzheimer’s disease (AD) is idiopathic, but accumulation of the protein amyloid-β (Aβ) is implicated in the disease pathology, particularly in the loss of neuronal synaptic function, which causes dementia in patients. Two studies in Science Signaling begin to untangle the mystery of how Aβ contributes to synaptic impairment. Park et al. found that a soluble form of Aβ impaired synaptic function by impeding Ca2+ clearance. Increased intracellular Ca2+ abundance activated the kinase CaMKIV. CaMKIV phosphorylated synapsin, a protein that links synaptic vesicles to actin to enable their transport. Phosphorylation of synapsin dissociated the vesicle-actin complex. Without the ability to transport synaptic components, neurons fail to maintain synaptic density or adjust synaptic strength in response to experience to form memories. Targeting CaMKIV might suppress the pathological effects of Aβ in AD. In addition to Aβ aggregates, neurofibrillary tangles of a phosphorylated form of the protein tau are seen in the brains of patients with AD. In the Archives, Amar et al. show how the 56-kDa oligomer Aβ*56, but not other forms of Aβ, stimulated an influx in intracellular Ca2+ that triggered the phosphorylation of tau at a site that promoted its aggregation. Various types of Aβ oligomers emerge at different stages of AD; Aβ*56 is detected early, before some of the clinical symptoms of AD are present. These findings suggest that identifying stage-specific roles of Aβ oligomers may lead to improved therapies. Both studies suggest that Ca2+ signaling may mediate the neurotoxic effects of Aβ accumulation in AD patients.

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