Mechanisms of apoptosis in Alzheimers disease

Four million Americans currently suffer from Alzheimer's disease (AD), and experts estimate that 22 million people around the world will be so afflicted by 2025. Acetylcholinestase inhibitors dominate the current AD market driving value of this therapeutic class to over US$1.2 billion in 2001. Although current AD treatments center on treating symptoms, future strategies are more likely to modify the course of the disease (for a full analysis of AD therapeutics click here). The most widely accepted hypothesis on the etiopathogenesis of AD proposes that aggregates of beta amyloid (Abeta) form in the brain. Under normal conditions, the predominant amyloid peptide secreted is Abeta(1-40) with about 10-15% being the longer 1-42 form. In AD there appears to be an increase in the longer more toxic form which is proposed to trigger tau hyperphosphorylation and neural degeneration. Neurotoxicity is thought to be due to altered calcium regulation, mitochondrial damage and/or immune stimulation. One strategy for treating AD is the prevention of Abeta release or the blockade of it neurotoxic activity.

In the cell culture setting, the toxicity of Abeta has been characterized as either apoptotic or necrotic. Thus, Abeta is likely to trigger toxicity via multiple mechanisms, including the activation of caspases, a family of cysteine proteases that execute the apoptotic pathway. The three main apoptotic pathways identified thus far (the mitochondrial, endoplasmic reticulum (ER) stress, and death receptor pathways) are activated by caspase-9, -12, and -8, respectively. The mitochondrial pathway may also serve as a point of convergence for the other two pathways, since death receptor activation and ER stress can both lead to cytochrome c release from the mitochondria and subsequent caspase-9 activation. Once cleaved caspase-9 activates caspase-3, the primary executioner caspase although this caspase is also activated independently of the mitochondrial pathway by, for example, caspase-8.

Recently Daniel Lu and colleagues, as well as others, have reported that the Abeta precursor protein (APP) is a substrate for caspase cleavage producing C31, a cytotoxic C-terminal APP peptide of 31 amino acids residues in length unrelated to Abeta. Furthermore, there was evidence that this cleavage event and caspase activation occur in brains of AD but not in control individuals. In their most recent study Lu et al reported a relationship between C31-mediated cell death and Abeta-mediated toxicity. In particular Abeta was found to activate caspase cleavage of APP and cause subsequent C31-dependent cell death. Considering that C31 mediated in part the neurotoxic effects of Abeta, it was perhaps not surprising that C31- and Abeta-induced cell death was mediated by a common pathway involving the activation of caspase-8 and caspase-9 but not caspase-3. These finding have further parallels with the situation in the brains of AD patients that are characterized by only a moderate increase in caspase-3 activity.

This study is important since it demonstrates that not only is APP a source of cytotoxic Abeta but that it also contributes to the cytotoxic activity of Abeta by representing a source of C31. The activation of caspase-8 and –9 by Abeta and C31 may represent a therapeutic target for strategies designed to limit neural cell death in AD.

Entry date Tuesday, December 16, 2003

Adapted from Lu et al, J Neurochem. 2003 Nov;87(3):733-41.