Hu, NW; Corbett, GT; Moore, S; Klyubin, I; O'Malley, TT; Walsh, DM; Livesey, FJ; Hu, NW; Corbett, GT; Moore, S; Klyubin, I; O'Malley, TT; Walsh, DM; Livesey, FJ; Rowan, MJ; - view fewer (2018) Extracellular Forms of Aβ and Tau from iPSC Models of Alzheimer's Disease Disrupt Synaptic Plasticity. Cell Reports , 23 (7) pp. 1932-1938. 10.1016/j.celrep.2018.04.040.

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Abstract

The early stages of Alzheimer's disease are associated with synaptic dysfunction prior to overt loss of neurons. To identify extracellular molecules that impair synaptic plasticity in the brain, we studied the secretomes of human iPSC-derived neuronal models of Alzheimer's disease. When introduced into the rat brain, secretomes from human neurons with either a presenilin-1 mutation, amyloid precursor protein duplication, or trisomy of chromosome 21 all strongly inhibit hippocampal long-term potentiation. Synaptic dysfunction caused by presenilin-1 mutant and amyloid precusor protein duplication secretomes is mediated by Aβ peptides, whereas trisomy of chromosome 21 (trisomy 21) neuronal secretomes induce dysfunction through extracellular tau. In all cases, synaptotoxicity is relieved by antibody blockade of cellular prion protein. These data indicate that human models of Alzheimer's disease generate distinct proteins that converge at the level of cellular prion protein to induce synaptic dysfunction in vivo. Hu et al. find that human iPSC-derived neurons with autosomal dominant Alzheimer's disease mutations or trisomy of chromosome 21 release Aβ peptides and tau derivatives that each inhibit a form of long-term synaptic plasticity, LTP, in vivo. This disruption occurs via a common pathway that requires cellular prion protein.

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