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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    • "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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    ABSTRACT: The neuropeptides substance P, orexin A (hypocretin-1) and neurotensin are signaling molecules that influence brain activity. We examined their cerebrospinal fluid (CSF) levels in a study population consisting of Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 32), stable MCI (SMCI, n = 13), other dementias (n = 15), and healthy controls (n = 20). CSF substance P level was increased in AD patients compared to patients with other dementias and healthy controls (P < 0.05 and P < 0.01, respectively). Patients with other dementia or SMCI had lower CSF orexin A level than AD patients (both P < 0.05) and marginally lower level than healthy controls (both P = 0.05). CSF neurotensin level was similar in all groups. In the total study population (n = 80), CSF substance P level correlated positively with CSF levels of T-tau and P-tau, and in AD patients (n = 32), CSF substance P level correlated positively with CSF Aβ1-42 level. In conclusion, CSF substance P level was elevated in AD patients and correlated with CSF Aβ1-42 level, a well established marker of senile plaque pathology. The role of low CSF orexin A level in other dementias or SMCI needs to be explored in further studies.
    Neuroscience Letters 10/2015; 609. DOI:10.1016/j.neulet.2015.10.006 · 2.03 Impact Factor
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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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    ABSTRACT: Reduced levels of Substance P (SP), an endogenous neuropeptide endowed with neuroprotective and anti-apoptotic properties, have been found in brain and spinal fluid of Alzheimer's disease (AD) patients. Potassium (K+) channel dysfunction is implicated in AD development and the amyloid-β (Aβ)-induced up-regulation of voltage-gated potassium channel subunits could be considered a significant step in Aβ brain toxicity. The aim of this study was to evaluate whether SP could reduce, in vivo, Aβ-induced overexpression of Kv subunits. Rats were intracerebroventricularly infused with amyloid-β 25–35 (Aβ25–35, 20 µg) peptide. SP (50 µg/Kg, i.p.) was daily administered, for 7 days starting from the day of the surgery. Here we demonstrate that the Aβ infused rats showed impairment in cognitive performances in the Morris water maze task 4 weeks after Aβ25–35 infusion and that this impairing effect was prevented by SP administration. Kv1.4, Kv2.1 and Kv4.2 subunit levels were quantified in hippocampus and in cerebral cortex by Western blot analysis and immunofluorescence. Interestingly, SP reduced Kv1.4 levels overexpressed by Aβ, both in hippocampus and cerebral cortex. Our findings provide in vivo evidence for a neuroprotective activity of systemic administration of SP in a rat model of AD and suggest a possible mechanism underlying this effect.
    PLoS ONE 11/2013; 8(11):e78036. DOI:10.1371/journal.pone.0078036 · 3.23 Impact Factor
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