AβPP, apoptosis and Alzheimer's disease

Apoptosis is a physiological process of suicidal cell death that an organism employs to eliminate the cells it no longer requires. Large-scale apoptosis during neuronal development, which causes removal of unwanted cells, is crucial for the proper development of the nervous system [1]. The signals that induce apoptosis are not yet fully comprehended but the steps that lead to cell death are perhaps better understood. Induction of apoptosis triggers a cascade of events which activate several proteases and nucleases and results in cell shrinkage, chromosomal condensation, DNA fragmentation and eventual cell death. Neuronal cell death is a prominent feature of Alzheimer’s disease (AD) [2] and there is growing evidence that apoptosis may be responsible for it. However, in keeping up with the character of the field, the notion that apoptosis plays a role in neuronal cell loss in AD remains controversial [3]. The toxic effects of externally added Aβ on neuronal tissue culture cells have been occur in vivo remains to be conclusively shown. A study reported by Borghi et al., in this issue of JAD likes to suggest that intracellular accumulation of Aβ in the endoplasmic reticulum could be associated with apoptosis. The presented data, however, fall short of such a conclusion and do not offer new insights into the role of amyloid β protein precursor (AβPP) in apoptosis in AD. Several studies have suggested that AβPP and Presenilins, which help to cleave AβPP at the γ-secretase site, are associated with apoptosis although the precise molecular mechanism by which these proteins cause neuronal apoptosis is not clear [4]. Expression of AβPP carrying FAD mutations is shown to cause apoptosis in tissue culture cells and transgenic animals. Some studies have suggested that these effects of AβPP may be mediated by the Aβ fragment while other studies have indicated that the C-terminal domain of AβPP could be involved in apoptosis [5–7]. The cytoplasmic region of AβPP (AβPP-CTF) that interacts with heterotrimeric G proteins has been implicated in apoptosis [8]. Furthermore, the AβPP-CTF domain can be cleaved by caspase 3 to release the cytoplasmic 31-residue fragment which in itself is shown to promote apoptosis [6] whereas a recent study [7] has provided evidence that the juxtamembrane domain of AβPP released after the caspase cleavage also causes apoptosis in vivo and in vitro. Moreover, a study by Passer et al. that appeared in JAD provided strong evidence that the cytoplasmic fragment of AβPP released after γ-cleavage (Cγ) induces apoptosis in vitro in tissue culture cells [5]. There has been growing interest in the Cγ fragment of AβPP because its generation resembles the process of ‘regulated membrane proteolysis’ which is a evolutionarily conserved mechanism of gene regulation [9]. Using a variety of techniques Passer et al., showed that the 59or 57-residue long γ-cleaved fragment of AβPP was strongly apoptotic or proapoptotic in several cell lines. Thus, the current data have implicated various cytoplasmic peptides of AβPP including Aβ, Cγ and fragments thereof in causation of apoptosis Fig. 1. There is also considerable data that mutations in presenilins associated with FAD are also involved in apoptosis [10]. It is not clear whether presenilins play a role in apoptosis by increasing the production of Aβ and Cγ or by altering Ca homeostasis and impairing mitochondrial function. Borghi et al., induced apoptosis by treating neuroblastoma cells with staurosporine and found that Aβ was significantly accumulated inside the cells. Although Aβ is mostly found accumulated in the extracellular senile plaques, recent studies have identified intracellular pools of Aβ and it has been proposed that Aβ toxicity may be caused by the intracellular pool [10]. The data of Borghi et al., offer some hints that Aβ may be accumulated in the endoplasmic reticulum but, as the authors note, the data are not conclusive since it