scholarly journals Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Kreis ◽  
Jana Desloovere ◽  
Nuria Suelves ◽  
Nathalie Pierrot ◽  
Xavier Yerna ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Neuronal Loss ◽  
Gaba Release ◽  
Long Term Potentiation ◽  
Precursor Protein ◽  
Wild Type ◽  
Inhibitory Neurotransmission ◽  
Gaba Production ◽  
Synaptic Functions ◽  
Term Potentiation

AbstractThe function of the amyloid precursor protein (APP) is not fully understood, but its cleavage product amyloid beta (Aβ) together with neurofibrillary tangles constitute the hallmarks of Alzheimer’s disease (AD). Yet, imbalance of excitatory and inhibitory neurotransmission accompanied by loss of synaptic functions, has been reported much earlier and independent of any detectable pathological markers. Recently, soluble APP fragments have been shown to bind to presynaptic GABAB receptors (GABABRs), subsequently decreasing the probability of neurotransmitter release. In this body of work, we were able to show that overexpression of wild-type human APP in mice (hAPPwt) causes early cognitive impairment, neuronal loss, and electrophysiological abnormalities in the absence of amyloid plaques and at very low levels of Aβ. hAPPwt mice exhibited neuronal overexcitation that was evident in EEG and increased long-term potentiation (LTP). Overexpression of hAPPwt did not alter GABAergic/glutamatergic receptor components or GABA production ability. Nonetheless, we detected a decrease of GABA but not glutamate that could be linked to soluble APP fragments, acting on presynaptic GABABRs and subsequently reducing GABA release. By using a specific presynaptic GABABR antagonist, we were able to rescue hyperexcitation in hAPPwt animals. Our results provide evidence that APP plays a crucial role in regulating inhibitory neurotransmission.

Similar levels of long-term potentiation in amyloid precursor protein -null and wild-type mice in the CA1 region of picrotoxin treated slices

2000 ◽  
Vol 288 (1) ◽  
pp. 9-12 ◽  
Author(s):  
Stephen M Fitzjohn ◽  
Robin A Morton ◽  
Frederick Kuenzi ◽  
Ceri H Davies ◽  
Guy R Seabrook ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Long Term Potentiation ◽  
Precursor Protein ◽  
Wild Type ◽  
Ca1 Region ◽  
Term Potentiation

scholarly journals Aβ-induced synaptic injury is mediated by presynaptic expression of amyloid precursor protein (APP) in hippocampal neurons

2020 ◽  
Author(s):  
Elena Vicario-Orri ◽  
Kensaku Kasuga ◽  
Sheue-Houy Tyan ◽  
Karen Chiang ◽  
Silvia Viana da Silva ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Hippocampal Neurons ◽  
Kinase Inhibitors ◽  
Light And Electron Microscopy ◽  
Long Term Potentiation ◽  
Precursor Protein ◽  
Plaque Deposition ◽  
Fyn Kinase ◽  
Term Potentiation ◽  
Ca3 Neurons

ABSTRACTThe patterns of Aβ-induced synaptic injury were examined after targeting of the amyloid precursor protein (APP) preferentially to either CA1 or CA3 neurons using Cre-lox technology combined with tetracycline-regulated expression. Both CA1- and CA3-APP-expressing transgenic mouse lines exhibited reduction in long-term potentiation (LTP) only when APP was expressed in neurons presynaptic to the recording site, whereas LTP remained comparable to wild-type mice when APP was expressed in postsynaptic neurons. As quantified by both light and electron microscopy, this orientation-specific impairment in synaptic plasticity was mirrored by synaptic loss in regions receiving axonal inputs from neurons expressing APP. Furthermore, A(plaque deposition also occurred only in the postsynaptic axonal fields of APP-expressing neurons. These deficits were reversed not only with doxycycline to inhibit APP expression but also with γ-secretase and Fyn kinase inhibitors, supporting the interpretation that the observed synaptic injury was mediated by Aβ. Taken together, these results demonstrate that APP/Aβ-induced synaptic toxicity is preferentially initiated by signaling of presynaptically expressed APP to the postsynaptic compartment.

P4-069: Secreted Amyloid Precursor Protein-Alpha Enhances Long-Term Potentiation Via Protein Synthesis- and Protein Trafficking-Dependent Mechanisms

2016 ◽  
Vol 12 ◽  
pp. P1040-P1040
Author(s):  
Karen D. Parfitt ◽  
Bruce Mockett ◽  
Timothy J. Hintz ◽  
Katie Bourne ◽  
Joanna M. Williams ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amyloid Precursor Protein ◽  
Protein Trafficking ◽  
Long Term Potentiation ◽  
Precursor Protein ◽  
Term Potentiation

scholarly journals Depression-like behaviors induced by defective PTPRT activity through dysregulated synaptic functions and neurogenesis

2020 ◽  
Vol 133 (20) ◽  
pp. jcs243972
Author(s):  
So-Hee Lim ◽  
Sangyep Shin ◽  
Myoung-Hwan Kim ◽  
Eung Chang Kim ◽  
Da Yong Lee ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Tyrosine Phosphorylation ◽  
Hippocampal Neurons ◽  
Granule Cells ◽  
Long Term Potentiation ◽  
Hippocampal Neurogenesis ◽  
Wild Type ◽  
Synaptic Functions ◽  
Term Potentiation ◽  
Deficient Mice

ABSTRACTPTPRT has been known to regulate synaptic formation and dendritic arborization of hippocampal neurons. PTPRT−/− null and PTPRT-D401A mutant mice displayed enhanced depression-like behaviors compared with wild-type mice. Transient knockdown of PTPRT in the dentate gyrus enhanced the depression-like behaviors of wild-type mice, whereas rescued expression of PTPRT ameliorated the behaviors of PTPRT-null mice. Chronic stress exposure reduced expression of PTPRT in the hippocampus of mice. In PTPRT-deficient mice the expression of GluR2 (also known as GRIA2) was attenuated as a consequence of dysregulated tyrosine phosphorylation, and the long-term potentiation at perforant–dentate gyrus synapses was augmented. The inhibitory synaptic transmission of the dentate gyrus and hippocampal GABA concentration were reduced in PTPRT-deficient mice. In addition, the hippocampal expression of GABA transporter GAT3 (also known as SLC6A11) was decreased, and its tyrosine phosphorylation was increased in PTPRT-deficient mice. PTPRT-deficient mice displayed reduced numbers and neurite length of newborn granule cells in the dentate gyrus and had attenuated neurogenic ability of embryonic hippocampal neural stem cells. In conclusion, our findings show that the physiological roles of PTPRT in hippocampal neurogenesis, as well as synaptic functions, are involved in the pathogenesis of depressive disorder.

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