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Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex
Katalin Völgyi1, Péter Gulyássy2, Mihail Ivilinov Todorov3,4
1MTA-ELTE NAP B Laboratory of Molecular and Systems Neurobiology, Institute of Biology, Hungarian Academy of Sciences and Eötvös Loránd University, Pázmány Péter sétány 1C, Budapest, H-1117, Hungary. katvolgyi@gmail.com.
Abstract:
Chronic cerebral hypoperfusion (CCH) evokes mild cognitive impairment (MCI) and contributes to the progression of vascular dementia and Alzheimer's disease (AD). How CCH induces these neurodegenerative processes that may spread along the synaptic network and whether they are detectable at the synaptic proteome level of the cerebral cortex remains to be established. In the present study, we report the synaptic protein changes in the cerebral cortex after stepwise bilateral common carotid artery occlusion (BCCAO) induced CCH in the rat. The occlusions were confirmed with magnetic resonance angiography 5 weeks after the surgery. Synaptosome fractions were prepared using sucrose gradient centrifugation from cerebral cortex dissected 7 weeks after the occlusion. The synaptic protein differences between the sham operated and CCH groups were analyzed with label-free nanoUHPLC-MS/MS. We identified 46 proteins showing altered abundance due to CCH. In particular, synaptic protein and lipid metabolism, as well as GABA shunt-related proteins showed increased while neurotransmission and synaptic assembly-related proteins showed decreased protein level changes in CCH rats. Protein network analysis of CCH-induced protein alterations suggested the importance of increased synaptic apolipoprotein E (APOE) level as a consequence of CCH. Therefore, the change in APOE level was confirmed with Western blotting. The identified synaptic protein changes would precede the onset of dementia-like symptoms in the CCH model, suggesting their importance in the development of vascular dementia.
Insights
Chronic cerebral hypoperfusion (CCH) alters synaptic proteins in the rat brain, impacting metabolism and neurotransmission. These synaptic changes may precede dementia, highlighting their role in vascular dementia development.
Area of Science:
- Neuroscience
- Proteomics
- Vascular Biology
Background:
- Chronic cerebral hypoperfusion (CCH) is linked to mild cognitive impairment (MCI), vascular dementia, and Alzheimer's disease (AD).
- The mechanisms by which CCH induces neurodegeneration and its synaptic proteome-level changes in the cerebral cortex are not fully understood.
Purpose of the Study:
- To investigate synaptic protein alterations in the cerebral cortex following CCH induced by bilateral common carotid artery occlusion (BCCAO) in a rat model.
- To determine if these synaptic changes precede the onset of dementia-like symptoms.
Main Methods:
- Rats underwent stepwise BCCAO to induce CCH, with occlusion confirmed via magnetic resonance angiography.
- Synaptosome fractions were isolated from the cerebral cortex 7 weeks post-occlusion.
- Label-free nanoUHPLC-MS/MS was used to analyze synaptic protein differences between CCH and sham-operated groups.
Main Results:
- 46 proteins showed altered abundance in CCH rats.
- Increased levels of synaptic protein/lipid metabolism and GABA shunt-related proteins were observed.
- Decreased levels of neurotransmission and synaptic assembly-related proteins were identified.
- Elevated synaptic apolipoprotein E (APOE) levels were implicated through network analysis and confirmed by Western blotting.
Conclusions:
- CCH induces significant synaptic protein changes in the cerebral cortex.
- Altered synaptic proteins, particularly APOE, may play a crucial role in the early stages of vascular dementia.
- These synaptic proteome changes precede dementia-like symptoms, offering potential biomarkers for early detection.
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