Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate.

Abstract

Amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer's disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aβ production. High nanomolar synthetic oligomeric Aβ42 also suppresses Pr at the SC-CA1 synapse in wild-type mice. This Aβ-induced suppression of Pr is mainly due to an mGluR5-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PIP2) in axons. Selectively inhibiting Aβ-induced PIP2 hydrolysis in the CA3 region of the hippocampus strongly prevents oligomeric Aβ-induced suppression of Pr at the SC-CA1 synapse and rescues synaptic and spatial learning and memory deficits in APP/PS1 mice. These results first reveal the presynaptic mGluR5-PIP2 pathway whereby oligomeric Aβ induces early synaptic deficits in AD.

• Authors: Yang He, Mengdi Wei, Yan Wu, Huaping Qin, Weinan Li, Xiaolin Ma, Jingjing Cheng, Jinshuai Ren, Ye Shen, Zhong Chen, Binggui Sun, Fu-De Huang, Yi Shen, Yu-Dong Zhou
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 1193 (03 13 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 30867420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Grm5 protein, mouse
• Peptide Fragments
• Phosphatidylinositol 4,5-Diphosphate
• Presenilin-1
• Receptor, Metabotropic Glutamate 5
• amyloid beta-protein (1-42)
• presenilin 1, mouse

Topics

• Alzheimer Disease (pathology, physiopathology)
• Amyloid beta-Peptides (genetics, metabolism)
• Animals
• CA1 Region, Hippocampal (metabolism, pathology, physiopathology)
• Cognition (physiology)
• Disease Models, Animal
• Embryo, Mammalian
• Humans
• Male
• Maze Learning (physiology)
• Memory (physiology)
• Mice
• Mice, Transgenic
• Peptide Fragments (genetics, metabolism)
• Phosphatidylinositol 4,5-Diphosphate (metabolism)
• Presenilin-1 (genetics, metabolism)
• Presynaptic Terminals (metabolism, pathology)
• Primary Cell Culture
• Protein Multimerization
• Pyramidal Cells (metabolism, pathology)
• Receptor, Metabotropic Glutamate 5 (metabolism)
• Synapses (metabolism, pathology)