Editors' ChoiceAlzheimer’s Disease

New connections: Amyloid-β in the pathology of Alzheimer’s disease

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Science Signaling  20 Mar 2018:
Vol. 11, Issue 522, eaat6003
DOI: 10.1126/scisignal.aat6003

Two studies in this issue of Science Signaling identify how amyloid-β causes various pathological mechanisms in mouse models of Alzheimer’s disease.

Alzheimer’s disease (AD) is a complex neurodegenerative disease characterized by progressive cognitive impairment and dementia. It’s not clear what causes AD, but the formation of plaques (focal aggregates) of the protein amyloid-β (Aβ) in the brain is frequently observed in AD patients, as are acetylation and aggregation of the protein tau and loss of the prolyl isomerase Pin1. Previous studies published in Science Signaling revealed how Aβ impairs synaptic function, which underlies dementia, by increasing calcium retention in neurons (see Ferrarelli). In this week’s issue of Science Signaling, Stallings et al. found that increased calcium abundance in neurons exposed to Aβ causes the loss of Pin1 activity by stimulating the phosphatase calcineurin. Pin1 regulates the activity of numerous proteins, notably those associated with postsynaptic function in neurons, and synaptic function is critically dependent on the maturation of structures called dendritic spines. Calcineurin dephosphorylated and inactivated Pin1, leading to the loss of mature dendritic spines in neurons. Treating mice with tacrolimus, a drug that inhibits calcineurin and is currently used to prevent rejection of organ transplants, prevented Aβ-induced dendritic spine loss. Also in this week’s issue of Science Signaling, Sen et al. linked Aβ, tau aggregates, and nitrosative stress in a mechanism underlying the synaptic and cognitive impairments associated with AD. In cortical neurons in mice or in culture, exposure to Aβ induced the production of nitric oxide, which promoted the nitrosylation of the glycolytic enzyme GAPDH and subsequently the activation of the acetylase p300 and inactivation of SIRT1, which together enhanced the acetylation and subsequent aggregation of tau. Treating mice with omigapil, a drug that blocks GAPDH nitrosylation and is currently being tested for the treatment of muscular dystrophy, reduced Aβ-induced tau acetylation and aggregation in the brain and improved their performance in learning and memory tests. These findings link some common phenotypes in AD to reveal precise pathological mechanisms of Aβ. They further identify new targets that may lead to therapies, including opportunities to repurpose already available drugs, for AD patients.

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