Kisspeptin Prevention of Amyloid-β Peptide Neurotoxicityin Vitro

Abstract

Alzheimer's disease (AD) onset is associated with changes in hypothalamic-pituitary−gonadal (HPG) function. The 54 amino acid kisspeptin (KP) peptide regulates the HPG axis and alters antioxidant enzyme expression. The Alzheimer's amyloid-β (Aβ) is neurotoxic, and this action can be prevented by the antioxidant enzyme catalase. Here, we examined the effects of KP peptides on the neurotoxicity of Aβ, prion protein (PrP), and amylin (IAPP) peptides. The Aβ, PrP, and IAPP peptides stimulated the release of KP and KP 45−54. The KP peptides inhibited the neurotoxicity of Aβ, PrP, and IAPP peptides, via an action that could not be blocked by kisspeptin-receptor (GPR-54) or neuropeptide FF (NPFF) receptor antagonists. Knockdown of KiSS-1 gene, which encodes the KP peptides, in human neuronal SH-SY5Y cells with siRNA enhanced the toxicity of amyloid peptides, while KiSS-1 overexpression was neuroprotective. A comparison of the catalase and KP sequences identified a similarity between KP residues 42−51 and the region of catalase that binds Aβ. The KP peptides containing residues 45−50 bound Aβ, PrP, and IAPP, inhibited Congo red binding, and were neuroprotective. These results suggest that KP peptides are neuroprotective against Aβ, IAPP, and PrP peptides via a receptor independent action involving direct binding to the amyloid peptides. KEYWORDS: KiSS-1, kisspeptin, amyloid-β, prion protein, amylin, neuroprotection N euroendocrine hormone changes are seen in aging, and there are disease specific changes associated with Alzheimer's disease (AD). 1,2 One of the neuroendocrine systems to show profound changes with aging is the hypothalamic−pituitary−gonadal (HPG) system, and the pathology of AD, Creutzfeldt−Jakob disease (CJD), and type 2 diabetes mellitus (T2DM) is also associated with changes in the hormones of this system. 3,4 A major regulator of the HPGaxis is the 54 amino acid kisspeptin (KP) peptide, which acts on gonadotrophin-releasing hormone (GnRH) neurons to activate GnRH release. 5 The KP peptide is produced in neurons by processing of the KiSS-1 preproprotein to yield the 54 amino acid KP peptide, which corresponds to residues 68−121 of KiSS-1. 6 Shorter derivatives of KP peptide comprising the C-terminal 14 (KP 41−54), 13 (KP 42−54), and 10 (KP 45−54) amino acids have also been found in tissues and corresponding to residues 108− 121, 109−121, and 112−121 of KiSS-1. 6,7 Biological activity of KP peptides requires the KP 45−54 sequence and is mediated via a specific KP receptor (GPR-54). 6,7 Lack of KP signaling via the GPR-54 receptor is associated with reproductive system failure. 8 Cleavage of the KP 45−54 peptide between residues 51 and 52 by matrix metalloproteinases abolishes the activation of GPR-54 by the KP 45−54 peptide. 9 The KP 42−54 and KP 45−54 peptides also activate NPFF receptors, 10,11 and some of the actions of KP peptides could be mediated by NPFF receptor activation.There are profound changes in KP signaling at menopause 12 and notable sex differences in hypothalamic neurodegenera...

Fibril formation and toxicity of the non-amyloidogenic rat amylin peptide

“…Polymorphism of human amylin fibrils (Goldsbury et al, 1999;Luca et al, 2007;Milton and Harris, 2010) together with the related Alzheimer's amyloid-␤ (A␤) fibrils (Milton and Harris, 2009) and Creutzfeldt-Jakob disease associated prion protein (PrP) fibrils (Minaki et al, 2009) restricts their use for drug screening. Molecular self-assembly of synthetic human amylin, A␤ or PrP also shows batch-to-batch variability with considerable variability in the fibrillar structures formed (Goldsbury et al, 1999;Zagorski et al, 1999;Luca et al, 2007;Harris, 2009, 2010;Minaki et al, 2009).…”

“…Human amylin fibrils are toxic to a range of cell types (Kawahara et al, 2000;Ritzel et al, 2007Ritzel et al, , 2010Law et al, 2010;Jhamandas and MacTavish, 2012) and we have determined whether rat amylin fibrils identified in the TEM study share this property in pancreatic islet and neuronal cell cultures. Compounds that mimic the catalase amyloid-binding domain have been shown to be protective against human amylin, A␤ and PrP toxicity (Milton et al, , 2012Habib et al, 2010). We have therefore also screened a peptide derivative of this catalase domain, peptide R9, which is known to block A␤ binding to catalase (Milton and Harris, 2009), to determine if it was capable of modifying actions of rat amylin fibrils in cell cultures.…”

“…Compounds that mimic the catalase amyloid-binding domain have been shown to be protective against human amylin, A␤ and PrP toxicity (Milton et al, , 2012Habib et al, 2010). We have therefore also screened a peptide derivative of this catalase domain, peptide R9, which is known to block A␤ binding to catalase (Milton and Harris, 2009), to determine if it was capable of modifying actions of rat amylin fibrils in cell cultures.…”

Putative Prophylaxes Updated of Placenta Extract and Aloe vera as Biogenic Stimulants

“…The KP peptides containing residues 45-50 (YNWNSF) bound Aβ, PrP, and IAPP, inhibited Congo red binding, and were neuroprotective. These results suggest that KP peptides are neuroprotective against Aβ, IAPP, and PrP peptides via a receptor independent action involving direct binding to the amyloid peptides [26] .…”

A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

“…Interestingly, kisspeptin, a physiological peptide sharing some structural similarities with CAβBD, was shown to ameliorate Aβ toxicity in the same way. This finding raises a question, whether kisspeptin plays a part in Aβ detoxification in vivo [171].…”