Human Brain-Derived Aß Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP.
J Neurosci
; 37(49): 11947-11966, 2017 12 06.
Article
in En
| MEDLINE
| ID: mdl-29101243
ABSTRACT
Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD) and several theories have been advanced to explain the relationship. A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid ß-protein (Aß), self-associates to form soluble aggregates that impair synaptic and network activity. Here, we used the most disease-relevant form of Aß, protein isolated from AD brain. Using this material, we show that the synaptotoxic effects of Aß depend on expression of APP and that the Aß-mediated impairment of synaptic plasticity is accompanied by presynaptic effects that disrupt the excitatory/inhibitory (E/I) balance. The net increase in the E/I ratio and inhibition of plasticity are associated with Aß localizing to synapses and binding of soluble Aß aggregates to synapses requires the expression of APP. Our findings indicate a role for APP in AD pathogenesis beyond the generation of Aß and suggest modulation of APP expression as a therapy for AD.SIGNIFICANCE STATEMENT Here, we report on the plasticity-disrupting effects of amyloid ß-protein (Aß) isolated from Alzheimer's disease (AD) brain and the requirement of amyloid precursor protein (APP) for these effects. We show that Aß-containing AD brain extracts block hippocampal LTP, augment glutamate release probability, and disrupt the excitatory/inhibitory balance. These effects are associated with Aß localizing to synapses and genetic ablation of APP prevents both Aß binding and Aß-mediated synaptic dysfunctions. Our results emphasize the importance of APP in AD and should stimulate new studies to elucidate APP-related targets suitable for pharmacological manipulation.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptide Fragments
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Synapses
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Brain
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Alzheimer Disease
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Neuronal Plasticity
Limits:
Aged
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Aged80
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Animals
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Female
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Humans
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Male
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Middle aged
Language:
En
Journal:
J Neurosci
Year:
2017
Document type:
Article