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Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms.

ABSTRACT: Overexpression of the amyloid precursor protein (APP) in hippocampal neurons leads to elevated beta-amyloid peptide (Abeta) production and consequent depression of excitatory transmission. The precise mechanisms underlying APP-induced synaptic depression are poorly understood. Uncovering these mechanisms could provide insight into how neuronal function is compromised before cell death during the early stages of Alzheimer's disease. Here we verify that APP up-regulation leads to depression of transmission in cultured hippocampal autapses; and we perform whole-cell recording, FM imaging, and immunocytochemistry to identify the specific mechanisms accounting for this depression. We find that APP overexpression leads to postsynaptic silencing through a selective reduction of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated currents. This effect is likely mediated by Abeta because expression of mutant APP incapable of producing Abeta did not depress transmission. In addition, although we eliminate presynaptic silencing as a mechanism underlying APP-mediated inhibition of transmission, we did observe an Abeta-induced presynaptic deficit in vesicle recycling with sustained stimulation. These findings demonstrate that APP elevation disrupts both presynaptic and postsynaptic compartments.

SUBMITTER: Ting JT

PROVIDER: S-EPMC1765464 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

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Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms.

Ting Jonathan T JT Kelley Brooke G BG Lambert Talley J TJ Cook David G DG Sullivan Jane M JM

Proceedings of the National Academy of Sciences of the United States of America 20061221 1

Overexpression of the amyloid precursor protein (APP) in hippocampal neurons leads to elevated beta-amyloid peptide (Abeta) production and consequent depression of excitatory transmission. The precise mechanisms underlying APP-induced synaptic depression are poorly understood. Uncovering these mechanisms could provide insight into how neuronal function is compromised before cell death during the early stages of Alzheimer's disease. Here we verify that APP up-regulation leads to depression of tra ...[more]

PMID: 17185415

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Project description:Leukocyte common antigen-receptor protein tyrosine phosphatases (LAR-RPTPs) are hub proteins that organize excitatory and inhibitory synapse development through binding to various extracellular ligands. Here, we report that knockdown (KD) of the LAR-RPTP family member PTP? reduced excitatory synapse number and transmission in cultured rat hippocampal neurons, whereas KD of PTP? produced comparable decreases at inhibitory synapses, in both cases without altering expression levels of interacting proteins. An extensive series of rescue experiments revealed that extracellular interactions of PTP? with Slitrks are important for excitatory synapse development. These experiments further showed that the intracellular D2 domain of PTP? is required for induction of heterologous synapse formation by Slitrk1 or TrkC, suggesting that interaction of LAR-RPTPs with distinct intracellular presynaptic proteins, drives presynaptic machinery assembly. Consistent with this, double-KD of liprin-?2 and -?3 or KD of PTP? substrates (N-cadherin and p250RhoGAP) in neurons inhibited Slitrk6-induced, PTP?-mediated heterologous synapse formation activity. We propose a synaptogenesis model in presynaptic neurons involving LAR-RPTP-organized retrograde signaling cascades, in which both extracellular and intracellular mechanisms are critical in orchestrating distinct synapse types.SIGNIFICANCE STATEMENT In this study, we sought to test the unproven hypothesis that PTP? and PTP? are required for excitatory and inhibitory synapse formation/transmission, respectively, in cultured hippocampal neurons, using knockdown-based loss-of-function analyses. We further performed extensive structure-function analyses, focusing on PTP?-mediated actions, to address the mechanisms of presynaptic assembly at excitatory synaptic sites. Using interdisciplinary approaches, we systematically applied a varied set of PTP? deletion variants, point mutants, and splice variants to demonstrate that both extracellular and intracellular mechanisms are involved in organizing presynaptic assembly. Strikingly, extracellular interactions of PTP? with heparan sulfates and Slitrks, intracellular interactions of PTP? with liprin-? and its associated proteins through the D2 domain, as well as distinct substrates are all critical.

Dataset Information

Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms.

Publications

Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms.

Similar Datasets

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