Substance P activates ADAM9 mRNA expression and induces α-secretase-mediated amyloid precursor protein cleavage

Institute of Cell Biology and Neurobiology, CNR, Via del Fosso di Fiorano, 65, 00143 Rome, Italy.
Neuropharmacology (Impact Factor: 5.11). 04/2012; 62(5-6):1954-63. DOI: 10.1016/j.neuropharm.2011.12.025
Source: PubMed


Altered levels of Substance P (SP), a neuropeptide endowed with neuroprotective and anti-apoptotic properties, were found in brain areas and spinal fluid of Alzheimer's disease (AD) patients. One of the hallmarks of AD is the abnormal extracellular deposition of neurotoxic beta amyloid (Aβ) peptides, derived from the proteolytic processing of amyloid precursor protein (APP). In the present study, we confirmed, the neurotrophic action of SP in cultured rat cerebellar granule cells (CGCs) and investigated its effects on APP metabolism. Incubation with low (5 mM) potassium induced apoptotic cell death of CGCs and amyloidogenic processing of APP, whereas treatment with SP (200 nM) reverted these effects via NK1 receptors. The non-amyloidogenic effect of SP consisted of reduction of Aβ(1-42), increase of sAPPα and enhanced α-secretase activity, without a significant change in steady-state levels of cellular APP. The intracellular mechanisms whereby SP alters APP metabolism were further investigated by measuring mRNA and/or steady-state protein levels of key enzymes involved with α-, β- and γ-secretase activity. Among them, Adam9, both at the mRNA and protein level, was the only enzyme to be significantly down-regulated following the induction of apoptosis (K5) and up-regulated after SP treatment. In addition to its neuroprotective properties, this study shows that SP is able to stimulate non-amyloidogenic APP processing, thereby reducing the possibility of generation of toxic Aβ peptides in brain.

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Available from: Cinzia Severini, Jan 11, 2016
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    • "Furthermore, substance P administration improved memory functions [2] [3] and prevented aging-related memory decline [4]. Substance P also stimulates non-amyloidogenic APP processing, which might reduce the generation of toxic Aβ peptides [28]. In postmortem AD brains, decreased substance P immunoreactivity has been observed in most studies [6] [7]. "
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    • "In addition to the well known neuroprotective properties of SP, we recently demonstrated that SP was able to decrease Aβ25–35-induced neuronal death in rat cerebellar granule neurons through a selective regulation of the Kv4.2 and Kv4.3 channel subunits overexpressed by Aβ25–35 exposure [41]. We also demonstrated that, in the same neurons, SP stimulates non-amyloidogenic APP processing, thereby reducing the possibility of generation of toxic Aβ peptides in brain [60]. It thus appears that the toxic effect of Aβ and the neuroprotective effect of SP may be ascribed, at least in part, to their opposite actions on these currents. "
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