Death and survival of neuronal cells exposed to Alzheimer's insults

Abstract

Neuronal cell death is the central abnormality occurring in brains suffering from Alzheimer's disease (AD). The notion that AD is a disease caused by loss of neurons points toward suppression of neuronal death as the most important therapeutic target. Nevertheless, the mechanisms for neuronal death in AD are still relatively unclear. Three known mutant genes cause familial AD (FAD): amyloid precursor protein, presenilin 1, and presenilin 2. Detailed analysis of cytotoxic mechanisms of the FADlinked mutant genes reveals that they cause neuronal cell death at physiologically low expression levels. Unexpectedly, cytotoxic mechanisms vary depending on the type of mutations and genes, suggesting that various mechanisms for neuronal cell death are involved in AD patients. In support of this, activity-dependent neurotrophic factor, basic fibroblast growth factor, and insulin-like growth factor-I can completely protect neurons from ␤-amyloid (A␤) cytotoxicity but exhibit incomplete or little effect on cytotoxicity by FAD mutant genes. By contrast, Humanin, a newly identified 24-residue peptide, suppresses neuronal cell death by various FAD mutants and A␤, whereas this factor has no effect on cytotoxicity from AD-irrelevant insults. Studies investigating death and survival of neuronal cells exposed to AD insults will open a new horizon in developing therapy aimed at neuroprotection.

SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase

“…In accordance with the finding that the V642I-APP-induced death is mediated by a signaling pathway that involves JNK (37,38,43,44), exogenous expression of V642I-APP increased the level of phosphorylated JNK (p-JNK) (Fig. 8C, lane 5).…”

“…duced death is intracellularly mediated by apoptosis signal-stimulating kinase-1 (ASK1) and JNK (37,38,43,44). Given that Humanin also inhibits caASK1-and caJNK-triggered neuronal cell death (37, 38), we first examined whether expression of SH3BP5 prevents this cell death.…”

Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis

“…HN binds to IGFBP-3 with high affinity and specificity in vitro, with Phe-6 being essential for the binding and also the antiapoptotic function in IGFBP-3-treated cells. Substitution of a critical cysteine residue at position 8 with alanine (HNA) completely destroys the protective activity of HN in AD-related in vitro systems (14,25). Notably, the residues important for IGFBP-3 binding are different, suggesting that HN acts in both IGFBP-3-dependent and independent fashion.…”

Humanin Binds and Nullifies Bid Activity by Blocking Its Activation of Bax and Bak

“…Synthetic HN Peptides Containing Membrane Penetration Sequences Suppress tBid-induced Apoptosis-Alternative theories have been proposed for explaining the cytoprotective mechanism of HN, involving either an extracellular role for HN via interactions with cell surface receptors (29) versus an intracellular role suppressing Bcl-2/Bax family proteins (30). To distinguish between these two mechanisms, we compared the activity of synthetic HN peptides containing versus lacking membrane-penetrating sequences with respect to their ability to inhibit caspase activation and apoptosis induced by overexpression of tBid.…”

“…HN was found to protect neuronal cells from a variety of toxic insults (26 -28). Some reports suggest that HN is secreted from cells and binds receptors in the plasma membrane (29). However, our laboratory showed previously that HN is present within the cytosol of cells where it can bind Bax and prevent the translocation of Bax from cytosol to mitochondria, thus providing protection from death stimuli that depend on this multidomain member of the Bcl-2/Bax family (30).…”