Characterization of a Bioactive Peptide T14 in the Human and Rodent Substantia Nigra: Implications for Neurodegenerative Disease
| Autor: | Susan Adele Greenfield, Giovanni Ferrati, Clive W. Coen, Auguste Vadisiute, Zoltan Molnár, Sara Garcia-Rates, Sally Frautschy, Gregory M. Cole |
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| Rok vydání: | 2022 |
| Předmět: |
acetylcholinesterase
T14 NBP14 dopamine substantia nigra Alzheimer’s disease Parkinson’s disease voltage sensitive dye imaging Organic Chemistry Neurodegenerative Diseases Rodentia General Medicine Catalysis Computer Science Applications Rats Inorganic Chemistry Substantia Nigra Acetylcholinesterase Animals Humans Physical and Theoretical Chemistry Peptides Molecular Biology Spectroscopy |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 21; Pages: 13119 |
| ISSN: | 1422-0067 |
| Popis: | The substantia nigra is generally considered to show significant cell loss not only in Parkinson’s but also in Alzheimer’s disease, conditions that share several neuropathological traits. An interesting feature of this nucleus is that the pars compacta dopaminergic neurons contain acetylcholinesterase (AChE). Independent of its enzymatic role, this protein is released from pars reticulata dendrites, with effects that have been observed in vitro, ex vivo and in vivo. The part of the molecule responsible for these actions has been identified as a 14-mer peptide, T14, cleaved from the AChE C-terminus and acting at an allosteric site on alpha-7 nicotinic receptors, with consequences implicated in neurodegeneration. Here, we show that free T14 is co-localized with tyrosine hydroxylase in rodent pars compacta neurons. In brains with Alzheimer’s pathology, the T14 immunoreactivity in these neurons increases in density as their number decreases with the progression of the disease. To explore the functional implications of raised T14 levels in the substantia nigra, the effect of exogenous peptide on electrically evoked neuronal activation was tested in rat brain slices using optical imaging with a voltage-sensitive dye (Di-4-ANEPPS). A significant reduction in the activation response was observed; this was blocked by the cyclized variant of T14, NBP14. In contrast, no such effect of the peptide was seen in the striatum, a region lacking the T14 target, alpha-7 receptors. These findings add to the accumulating evidence that T14 is a key signaling molecule in neurodegenerative disorders and that its antagonist NBP14 has therapeutic potential. |
| Databáze: | OpenAIRE |
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