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.

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.

Differential effects of protein kinase inhibitors on pre-established long-term potentiation in rat hippocampal neurons in vitro

1991 ◽  
Vol 121 (1-2) ◽  
pp. 259-262 ◽  
Author(s):  
Henry Matthies ◽  
Thomas Behnisch ◽  
Hiroshi Kase ◽  
Hansjürgen Matthies ◽  
Klaus G. Reymann
Keyword(s):  
Protein Kinase ◽  
Hippocampal Neurons ◽  
Kinase Inhibitors ◽  
Long Term Potentiation ◽  
Protein Kinase Inhibitors ◽  
Differential Effects ◽  
Term Potentiation

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

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

Specific involvement of Ca(2+)-calmodulin kinase II in cholinergic modulation of neuronal responsiveness

1992 ◽  
Vol 68 (6) ◽  
pp. 2264-2269 ◽  
Author(s):  
W. Muller ◽  
J. J. Petrozzino ◽  
L. C. Griffith ◽  
W. Danho ◽  
J. A. Connor
Keyword(s):  
Neuronal Excitability ◽  
Kinase Inhibitors ◽  
Cognitive Disorders ◽  
Long Term Potentiation ◽  
Muscarinic Agonists ◽  
Memory Mechanism ◽  
Term Potentiation ◽  
High Affinity Receptor ◽  
Dependent Protein ◽  
Ca3 Neurons

1. Muscarinic agonists when applied in the hippocampus at low concentrations suppress intrinsic controls on neuronal excitability through the block of Ca(2+)-activated K conductance(s), gK (Ca), underlying the adaptation of firing and slow afterhyperpolarization (sAHP) in CA1 and CA3 neurons. Carbachol, for example, is effective at 0.1-0.3 microM suggesting activation of a relatively high-affinity receptor. 2. We have examined the mechanism of this action by using a new, highly specific, peptide inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII) as well as other kinase inhibitors and show that the muscarinic block of gK (Ca) relies on CaMKII activation in both CA1 and CA3 neurons. Thus phosphorylation of these channels or of an intermediary protein causes the channels to remain closed in the presence of Ca2+ and depolarization. 3. The very similar electrophysiological effects of serotonergic and glutamatergic agonists are mediated either through other kinases or by entirely different processes. 4. Block of intrinsic phosphatase activity by okadaic acid also reduced adaptation and sAHP, and muscarinic agonists had no further effect on these quantities. 5. The removal of presynaptic cholinergic inputs to the hippocampus in animals has a deleterious effect on the performance of tasks requiring spatial memory and is also implicated as a cause of cognitive disorders in humans. By increasing Ca2+ accumulation during electrical activity and promoting CaMKII activity, muscarinic input provides parallel reinforcing pathways for the induction of long-term potentiation, an important cellular memory mechanism. This suggests a possible link between behavioral and cellular approaches to the analysis of learning and memory.

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