. An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiol Dis. 2006 Sep;23(3):669-78. PubMed.


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  1. This study shows that Aβ1-40 (as well as PrP106-126 peptide) induces ER stress, leading to apoptotic death in neurons. Previous studies have ruled out the primary role of ER stress in AD (e.g., Piccini et al., 2004). It would be interesting to ascertain if endogenous Aβ (produced through a Bri/Aβ fusion protein, e.g.) induces the same cascade of events described in the study. Then, check if Aβ1-42 has the same effects. Moreover, I would test the effect of different states of aggregation of Aβ peptides.

    View all comments by Massimo Tabaton
  2. Our lab previously reported activation of the UPR in AD neurons (Hoozemans et al., 2005). In the current paper, Ferreiro et al. show induction of BiP levels, as well as decreased pro-caspase-12 levels induced by Aβ1-40. This may indicate that the ER stress response (including the apoptotic branch of the UPR) is activated directly by Aβ, and may be the cause of the UPR activation that we observe in AD neurons. However, the data obtained by Ferreiro et al. in vitro appear not to corroborate fully with observations from the actual patient material. The data presented in the Ferreiro paper suggest that apoptotic cell death is a direct consequence of Aβ-induced UPR activation, whereas we find no evidence of apoptosis in AD neurons with an activated UPR. The UPR is activated as a protective mechanism to restore ER homeostasis, and although it can result in cell death after prolonged activation, it is not necessarily a bad thing. This is in agreement with our observation that the UPR is activated relatively early in AD pathology. In this respect it would be interesting to distinguish effects of Aβ aggregation state (here only a fibrillar preparation of Aβ1-40 was used). Therefore, this paper adds to the emerging idea that the ER and the ER stress response are involved in AD pathogenesis, but caution is warranted to directly translate these in vitro data to the disease mechanism.

    View all comments by Wiep Scheper
  3. The research community appears to play with half a deck of cards by ignoring the role of metals, particularly aluminum in co-causation of Alzheimer dementia. Ghribi et al., in a series of studies, investigated the effect of aluminum on the endoplasmic reticulum and mitochondria, and reported that the metal caused apoptosis through changes in cytochrome c, Bcl-2 and Bax in the hippocampus of aluminum-treated rabbits. There is cross-talk between the metal and amyloid, as the two toxins bond to each other, and the metal affects processing of amyloid. The aging brain has bio-accumulated a substantial amount of aluminum by age 60. Must we now move beyond a one-dimensional view of AD to make progress? Most chronic diseases of the aging process have multiple causation.

    View all comments by Erik Jansson
  4. In a recent review paper (Ghribi, 2006), we have addressed the role of ER in Alzheimer disease and discussed data supporting dysfunction of the ER as an early event leading to Aβ accumulation in familial AD. We have also discussed the possible role of oxidative stress and other factors as contributors in Aβ accumulation by reducing the clearance of Aβ from the endoplasmic reticulum. Our previous work (Ghribi et al., 2004; 2003) also demonstrated ER stress as a mechanism underlying exogenous Aβ neurotoxicity.

    View all comments by Othman Ghribi
  5. This paper shows the involvement of calcium released from the endoplasmic reticulum (ER) in neuronal death induced by a synthetic prion peptide and by the Aβ peptide as causative agents in prion and Alzheimer diseases, respectively. The work is done using cultured cortical neurons and demonstrates a cascade of events causing neuronal demise. This pathway is triggered by elevated calcium that can be blocked by inhibition of ER calcium channels.

    Calcium dysregulations have long been considered as a part of neuronal toxicity in AD, as also shown by mutations in presenilins. Likewise, infected cells in prion disease show calcium elevation but the mechanisms causing cell death have remained elusive. This paper shows a possible mechanism by which disturbed calcium regulation causes cell death through a crosstalk between the ER and mitochondria leading ultimately to caspase activation. The paper is highly recommended.

    View all comments by Dan Lindholm

This paper appears in the following:


  1. Aβ Assault on Neurons Targets ER, Calcium