Human Brain-Derived Aβ Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP.

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 β-protein (Aβ), self-associates to form soluble aggregates that impair synaptic and network activity. Here, we used the most disease-relevant form of Aβ, protein isolated from AD brain. Using this material, we show that the synaptotoxic effects of Aβ depend on expression of APP and that the Aβ-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 Aβ localizing to synapses and binding of soluble Aβ aggregates to synapses requires the expression of APP. Our findings indicate a role for APP in AD pathogenesis beyond the generation of Aβ and suggest modulation of APP expression as a therapy for AD.SIGNIFICANCE STATEMENT Here, we report on the plasticity-disrupting effects of amyloid β-protein (Aβ) isolated from Alzheimer's disease (AD) brain and the requirement of amyloid precursor protein (APP) for these effects. We show that Aβ-containing AD brain extracts block hippocampal LTP, augment glutamate release probability, and disrupt the excitatory/inhibitory balance. These effects are associated with Aβ localizing to synapses and genetic ablation of APP prevents both Aβ binding and Aβ-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.

• Authors: Zemin Wang, Rosemary J Jackson, Wei Hong, Walter M Taylor, Grant T Corbett, Arturo Moreno, Wen Liu, Shaomin Li, Matthew P Frosch, Inna Slutsky, Tracy L Young-Pearse, Tara L Spires-Jones, Dominic M Walsh
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 37 Issue 49 Pg. 11947-11966 (12 06 2017) ISSN: 1529-2401 [Electronic] United States
• PMID: 29101243 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 the authors 0270-6474/17/3711947-20$15.00/0.

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Peptide Fragments
• amyloid beta-protein (1-42)

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (metabolism, pathology)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (biosynthesis, deficiency)
• Animals
• Brain (metabolism, pathology)
• Excitatory Postsynaptic Potentials (physiology)
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Neuronal Plasticity (physiology)
• Organ Culture Techniques
• Peptide Fragments (metabolism)
• Protein Binding (physiology)
• Synapses (metabolism, pathology)