Neuronal cell death in Alzheimer's 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.

Keywords: Alzheimer’s disease; Humanin (HN); amyloid precursor protein (APP); amyloid β; neuronal death; neuroprotection; presenilin (PS).

Fig (1)

AD pathomechanism based on amyloid hypothesis and therapeutic strategies. Aβ is produced from APP by enzyme cleavage. Soluble and fibril Aβ species directly or indirectly cause neuronal death. Several anti-Aβ therapies are under development: inhibition of secretase activity, degradation of Aβ , and elimination of Aβ by immune response. In addition, direct inhibition of neuronal death by neuroprotective factors is another potential strategy for AD therapy.

Fig (2)

Progression of neuronal death in AD in various models. The relationship between neurotoxic insults (thin line) and neuronal cell death (bold line) is influenced by the neuroprotective function (dotted line) counteracting to neurotoxic insults (A). The degree of neuronal death is reduced reflecting the degree of insults or neuroprotection by anti-Aβ or neuroprotective treatment at the time of diagnosis (B, C). When treatments start at earlier time point, neuronal death may be prevented (D, E). X- and Y-axis indicate age and degree of each phenomenon, respectively. See text for details.

Fig (3)

Neuroprotective mechanisms of HN. Extracellular HN binds its putative receptor and activates intracellular signaling cascade(s). One of such effects inhibits JNK activity. Intracellular HN binds Bax and inhibits Bax-mediated apoptosis.