Study of mechanisms underlying the protective effects of artemisinins in Alzheimer’s disease with special reference to adult hippocampal neurogenesis
| Project code | PN-III-P4-PCE-2021-1089 | |
| No. contract | PCE 56 | |
| The title project | Study of mechanisms underlying the protective effects of artemisinins in Alzheimer’s disease with special reference to adult hippocampal neurogenesis | |
| acronym project | Artemisinins and neu | |
| Field |
LS5_7 – Neurological disorders (eg neurodegenerative diseases, seizures) LS5_3 – Neuronal development, plasticity and regeneration |
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| Abstract | The primarily anti-malarial artemisinins (ARMs) are promising multipotent drugs yet with unclear mechanisms of action. Recently we found that in male mice of an Alzheimer disease (AD)-model treatment with ARMs increased the level of key inhibitory synaptic proteins and upregulated the CDK5 activator p35. In addition to altered synaptic plasticity, adult hippocampal neurogenesis (AHN) is also affected in AD and restoring neurogenesis can enhance cognition and memory. GABAergic signaling is involved in all stages of AHN. Local interneurons are a main source of GABA and form first synapses onto adult born neurons playing a key role in controlling AHN. Furthermore, aberrant activity of CDK5 was associated with altered AHN in AD. In the present project we plan to clear whether: 1) increased GABAergic inputs after treatment with ARMs modulate expression levels of key markers of AHN at different developmental stages of AD in correlation to inhibitory synaptic proteins, 2) ARMs specifically target specific GABAergic interneuron populations affecting their synaptic contacts with neuroblasts , 3) changes in AHN correlate to levels of GABA in CSF, 4) modulating the activity of CDK5 by ARMs correlate to changes in the expression of AHN-markers, and 5) the main findings in male mice parallel to those in female mice. Our studies will provide new important insights into the mechanisms underlying ARMs effects, allowing to elucidate their therapeutic potential in AD. | |
| The objective project | 1) To analyze the correlations between ARMs induced GABAergic changes and expression of developmental-phase specific markers of AHN in APP-PS1 mice at different ages, 2) To determine whether GABA levels in CSF correlate to changes in GABAergic synaptic proteins and/or markers of AHN3) To analyze the relationship between ARMs induced changes in p35/CK5 levels and expression of developmental-phase specific markers of AHN, and4) To check whether main findings in male mice correspond to those in female mice. |
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| Estimated results |
1. Relevant correlations between ARMs induced GABAergic changes and expression of developmental-phase specific markers of AHN in APP-PS1 mice at different ages. 2. GABA levels in CSF of APP-PS1 mice correlate to changes in GABAergic synaptic proteins and/or markers of AHN.3. Artemisinin therapy induced changes in p35/CK5 levels can be correlated to expression of developmental-phase specific markers of AHN. 4. Changes in inhibitory synaptic markers and AHN indicators in female mice partially or totally overlap with the findings in male APP-PS1 without and with artemisinin treatment. |
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| Start date contract | 02/06/2022 | |
| End date contract | 31/12/2024 | |
| Time project [ month ] |
31 | |
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Scientific report – Execution stage no. 1 / 2022
Scientific report – Execution stage no. 2 / 2023
Final Scientific Report and summary for the research project PCE56