RESUMO
The pons region of the Alzheimer's disease (AD) brain is one of the last to show amyloid-ß (Aß) 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 Aß 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 Aß deposits. Results showed Aß 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 Aß, whilst both KP and catalase can bind Aß, suggesting that colocalization in Aß deposits is not restricted to compounds that directly bind Aß. The neuroprotective actions of KP, CRH, and catalase were confirmed in vitro, and fibrillar Aß preparations were shown to stimulate the release of KP in vitro. In conclusion, neuroprotective KP, CRH, and catalase all colocalize with Aß plaque-like deposits in the pons region from a male AD subject.
RESUMO
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-ß (Aß) 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 Aß, prion protein (PrP), and amylin (IAPP) peptides. The Aß, PrP, and IAPP peptides stimulated the release of KP and KP 45-54. The KP peptides inhibited the neurotoxicity of Aß, 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 Aß. The KP peptides containing residues 45-50 bound Aß, PrP, and IAPP, inhibited Congo red binding, and were neuroprotective. These results suggest that KP peptides are neuroprotective against Aß, IAPP, and PrP peptides via a receptor independent action involving direct binding to the amyloid peptides.