Neuronal Cell Death in Alzheimers Disease and a Neuroprotective Factor, Humanin

Abstract

Brain atrophy caused by neuronal loss is a prominent pathological feature of Alzheimer's disease (AD). Amyloid beta (Abeta), the major component of senile plaques, is considered to play a central role in neuronal cell death. In addition to removal of the toxic Abeta, direct suppression of neuronal loss is an essential part of AD treatment; however, no such neuroprotective therapies have been developed. Excess amount of Abeta evokes multiple cytotoxic mechanisms, involving increase of the intracellular Ca(2+) level, oxidative stress, and receptor-mediated activation of cell-death cascades. Such diversity in cytotoxic mechanisms induced by Abeta clearly indicates a complex nature of the AD-related neuronal cell death. We have identified a 24-residue peptide, Humanin (HN), which suppresses in vitro neuronal cell death caused by all AD-related insults, including Abeta, so far tested. The anti-AD effect of HN has been further confirmed in vivo using mice with Abeta-induced amnesia. Altogether, such potent neuroprotective activity of HN against AD-relevant cytotoxicity both in vitro and in vivo suggests the potential clinical applications of HN in novel AD therapies aimed at controlling neuronal death.

The structure analysis of Humanin analog, AGA-(C8R)HNG17, by circular dichroism and sedimentation equilibrium: Comparison with the parent molecule

“…An attempt was made to directly dissolve the peptide at 2 mg/ml with PBS, which generated visible particulates and precipitates. It is evident that these peptides must be first dissolved in water, not PBS or other solvents, for high solubility, as has been done [1][2][3][4][5][6]. Thus, CD analysis was done using the stock solution of AGA-(C8R)HNG17 first dissolved in water.…”

“…A 24-amino acid peptide, Humanin (HN), is a novel peptide that protects neuronal cells in vitro and in vivo from neurotoxic insults involved in Alzheimer's diseases [1][2][3][4][5][6][7]. During structure-activity analysis, a single mutation in HN of Ser14 to Gly (HNG) was found to increase the activity 1000-fold [4][5][6].…”

“…Here we have characterized the structural properties of this short peptide analog by CD and sedimentation. First, its structure in water was examined by CD, since this as well as other HN-related peptides cannot be directly dissolved in PBS or cell culture medium [8] and have been dissolved in water prior to dilution into the cell culture media for the biological evaluation [1][2][3][4][5][6]. It is possible that the structure in water dictates the functional state of the peptide in the assay medium (PBS).…”

Humanin Protects Cortical Neurons from Ischemia and Reperfusion Injury by the Increased Activity of Superoxide Dismutase

“…It was originally found in the occipital lobe of an autopsied Alzheimer's disease (AD) patient [13][14][15]. Multiple studies demonstrated that humanin suppresses neuronal cell death caused by AD-specific insults, including both amyloid-beta (Abeta) peptides and familial AD-causative genes [26,31], by binding to a novel IL-6-receptor-related receptor(s) on the cell surface involving CNTFRalpha (ciliary neurotrophic factor receptor alpha), WSX-1 (IL-27 receptor subunit), and gp130 [16,28], and by preventing mitochondrial dysfunction [20]. This endogenous peptide can also activate the JAK2/ STAT3 signaling axis, triggering a signal transduction cascade linked to the inhibition of AD-related neurotoxicity [5].…”

Neuroprotective Protein and Carboxypeptidase E

“…One possibility is that CPE is required for the sorting and processing of proteins and peptides that promote cell survival such as activitydependent neuroprotective protein (ADNP; Gozes 2007), humanin, a peptide which suppresses cell death induced by Alzheimer's disease-related insults in vitro (Niikura et al 2006) and BDNF which may be attenuated in some neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease (Chao et al 2006;Zuccato and Cattaneo 2007).…”