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...

The pons region of the Alzheimer's disease (AD) brain is one of the last to show amyloid-β (Aβ) deposits and has been suggested to contain neuroprotective compounds. Kisspeptin (KP) is a hormone that activates the hypothalamic-pituitary-gonadal axis and has been suggested to be neuroprotective against Aβ toxicity. The localization of KP, plus the established endogenous neuroprotective compounds corticotropin releasing hormone (CRH) and catalase, in tissue sections from the pons region of a male AD subject has been determined in relation to Aβ deposits. Results showed Aβ deposits also stained with KP, CRH, and catalase antibodies. At high magnification the staining of deposits was either KP or catalase positive, and there was only a limited area of the deposits with KP-catalase colocalization. The CRH does not bind Aβ, whilst both KP and catalase can bind Aβ, suggesting that colocalization in Aβ deposits is not restricted to compounds that directly bind Aβ. The neuroprotective actions of KP, CRH, and catalase were confirmed in vitro, and fibrillar Aβ preparations were shown to stimulate the release of KP in vitro. In conclusion, neuroprotective KP, CRH, and catalase all colocalize with Aβ plaque-like deposits in the pons region from a male AD subject.

Recent studies have suggested that the kisspeptin (KP) and kissorphin (KSO) peptides have neuroprotective actions against the Alzheimer's amyloid-β (Aβ) peptide. Overexpression of the human KiSS-1 gene that codes for KP and KSO peptides in SH-SY5Y neurons has also been shown to inhibit Aβ neurotoxicity. The in vivo actions of KP include activation of neuroendocrine and neurotransmitter systems. The present study used antagonists of KP, neuropeptide FF (NPFF), opioids, oxytocin, estrogen, adrenergic, cholinergic, dopaminergic, serotonergic, and γ-aminobutyric acid (GABA) receptors plus inhibitors of catalase, cyclooxygenase, nitric oxide synthase, and the mitogen activated protein kinase cascade to characterize the KiSS-1 gene overexpression neuroprotection against Aβ cell model. The results showed that KiSS-1 overexpression is neuroprotective against Aβ and the action appears to involve the KP or KSO peptide products of KiSS-1 processing. The mechanism of neuroprotection does not involve the activation of the KP or NPFF receptors. Opioids play a role in the toxicity of Aβ in the KiSS-1 overexpression system and opioid antagonists naloxone or naltrexone inhibited Aβ toxicity. The mechanism of KiSS-1 overexpression induced protection against Aβ appears to have an oxytocin plus a cyclooxygenase dependent component, with the oxytocin antagonist atosiban and the cyclooxygenase inhibitor SC-560 both enhancing the toxicity of Aβ.

Alzheimer's disease, Familial British dementia, Familial Danish dementia, Type 2 diabetes mellitus, plus Creutzfeldt-Jakob disease are associated with amyloid fibril deposition and oxidative stress. The antioxidant enzyme catalase is a neuroprotective amyloid binding protein. Herein the effects of catalase overexpression in SH-SY5Y neuronal cells on the toxicity of amyloid-β (Aβ), amyloid-Bri (ABri), amyloid-Dan (ADan), amylin (IAPP), and prion protein (PrP) peptides were determined. Results showed catalase overexpression was neuroprotective against Aβ, ABri, ADan, IAPP, and PrP peptides. The catalase inhibitor 3-amino-1,2,4-triazole (3-AT) and catalase-amyloid interaction inhibitor benzothiazole aniline tetra(ethylene glycol) (BTA-EG4) significantly enhanced neurotoxicity of amyloid peptides in catalase overexpressing neuronal cells. This suggests catalase neuroprotection involves breakdown of hydrogen peroxide (H2O2) plus a direct binding interaction between catalase and the Aβ, ABri, ADan, IAPP, and PrP peptides. Kisspeptin 45-50 had additive neuroprotective actions against the Aβ peptide in catalase overexpressing cells. The effects of 3-AT had an intracellular site of action, while catalase-amyloid interactions had an extracellular component. These results suggest that the 3-AT and BTA-EG4 compounds may be able to inhibit endogenous catalase mediated neuroprotection. Use of BTA-EG4, or compounds that inhibit catalase binding to amyloid peptides, as potential therapeutics for Neurodegenerative diseases may therefore result in unwanted effects.

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