Excitotoxicity-induced expression of amyloid precursor protein (beta-APP) in the hippocampus and cortex of rat brain.
W Gordon-Krajcer1, B Gajkowska
1Department of Neurochemistry, Medical Research Centre, Polish Academy of Sciences, Warszawa.
Abstract:
After stereotaxic microinjection of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA) to CA1 of rat hippocampus, the animals were sacrificed: 0 h, 2 h, 12 h, 24 h and 3 days after the insult. Other groups of animals before microinjection of the excitotoxins received intraperitoneal injection of dizocilpine (MK-801). Expression of beta-APP was assessed by immunohistochemical and immunobiochemical methods, and the results were correlated with changes in tissue ultrastructure observed in the electron microscopy. The results of the immunochemical analyses study demonstrated that application of NMDA and AMPA resulted in the increase of the expression of beta-APP in the CA1 of hippocampus and to a less extent in the cortex. Pretreatment with MK-801 strongly suppressed this effect. Beta-amyloid release was not detected. Morphological and cytochemical study revealed that NMDA injection induced massive damage of hippocampal and cortical neurones, associated with mitochondrial calcium sequestration and unusual accumulation of neurofilaments. Ultrastructural changes after AMPA application were limited to the brain cortex. These data indicate that although excitotoxic insult induces hyperexpression of beta3-APP, there is no relation between this effect and neurodegeneration, and excitotoxicity does not induce amyloidogenic processing of beta-APP.
Insights
Excitotoxic insults like NMDA and AMPA increase beta-amyloid precursor protein (beta-APP) expression in the hippocampus but do not lead to beta-amyloid release or neurodegeneration. MK-801 pretreatment blocks this effect.
Area of Science:
- Neuroscience
- Neurobiology
- Cellular Biology
Background:
- Excitotoxicity, induced by agonists like NMDA and AMPA, is a key factor in neuronal damage.
- Beta-amyloid precursor protein (beta-APP) is implicated in neurodegenerative diseases.
- The relationship between excitotoxicity, beta-APP expression, and neurodegeneration requires further elucidation.
Purpose of the Study:
- To investigate the effect of NMDA and AMPA excitotoxicity on beta-APP expression in the rat hippocampus.
- To determine if excitotoxicity-induced beta-APP changes correlate with neurodegeneration.
- To assess the role of NMDA receptor antagonist MK-801 in modulating these responses.
Main Methods:
- Stereotaxic microinjection of NMDA or AMPA into the CA1 region of rat hippocampus.
- Immunohistochemical and immunobiochemical analysis of beta-APP expression at various time points.
- Electron microscopy for ultrastructural analysis of neuronal damage.
- Administration of dizocilpine (MK-801) as a pretreatment.
Main Results:
- NMDA and AMPA application significantly increased beta-APP expression in the hippocampus and cortex.
- MK-801 pretreatment markedly suppressed the NMDA/AMPA-induced increase in beta-APP.
- NMDA injection caused severe neuronal damage, mitochondrial calcium sequestration, and neurofilament accumulation.
- AMPA-induced ultrastructural changes were confined to the brain cortex.
- No beta-amyloid release was detected.
Conclusions:
- Excitotoxic insults elevate beta-APP expression but are not directly linked to neurodegeneration.
- Excitotoxicity does not appear to trigger the amyloidogenic processing of beta-APP.
- NMDA receptor antagonism effectively mitigates excitotoxicity-induced beta-APP upregulation.
