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

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...  Read more

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.

References:
Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W. The unfolded protein response is activated in Alzheimer's disease. Acta Neuropathol (Berl). 2005 Aug;110(2):165-72. Epub 2005 Jun 23. Abstract

Scheper W, Hol EM. Protein quality control in Alzheimer's disease: a fatal saviour. Curr Drug Targets CNS Neurol Disord. 2005 Jun;4(3):283-92. Review. Abstract

View all comments by Jeroen Hoozemans
View all comments by Wiep Scheper

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.

References:
Ghribi O, DeWitt DA, Forbes MS, Herman MM, Savory J. Co-involvement of mitochondria and endoplasmic reticulum in regulation of apoptosis: changes in cytochrome c, Bcl-2 and Bax in the hippocampus of aluminum-treated rabbits. Brain Res. 2001 Jun 8;903(1-2):66-73. Abstract

View all comments by Erik Jansson

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.

References:
Ghribi O. The role of the endoplasmic reticulum in the accumulation of beta-amyloid peptide in Alzheimer's disease. Curr Mol Med. 2006;6(1):119-33. Review. Abstract

Ghribi O, Herman MM, Pramoonjago P, Spaulding NK, Savory J. GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases. Neurobiol Dis. 2004;16(2):417-27. Abstract

Ghribi O, Herman MM, Savory J. Lithium inhibits Abeta-induced stress in endoplasmic reticulum of rabbit hippocampus but does not prevent oxidative damage and tau phosphorylation. J Neurosci Res. 2003;71(6):853-62. Abstract

View all comments by Othman Ghribi

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 is an excellent paper highlighting the importance of ER stress and related genes in motor neuron survival. The authors are able to uncover a previously ill-defined connection between one of the essential ER signaling arms (IRE/XBP-1) and an essential cellular function, autophagy. In this work, they define novel pathways by which molecular mechanisms underlying both fALS, and also importantly, sALS, could lead to motor neuron death. As happens in many other examples of pathogenesis, a physiological response (increased ER stress) can led to pathology exacerbation (lack of autophagic response). If this mechanism is consistently tested in other SOD mutants as well as other ALS models, the resulting outcome could shed light upon the development of novel therapeutic approaches.

Perhaps more interestingly, and as discussed by the authors, ALS pathology shares protein aggregation with other neurodegenerative diseases, such as Alzheimer’s and many others. Is the potential protective role of XBP downregulation also applicable to those diseases? The role of XBPs as a pro-aggregator...  Read more

This is an excellent paper highlighting the importance of ER stress and related genes in motor neuron survival. The authors are able to uncover a previously ill-defined connection between one of the essential ER signaling arms (IRE/XBP-1) and an essential cellular function, autophagy. In this work, they define novel pathways by which molecular mechanisms underlying both fALS, and also importantly, sALS, could lead to motor neuron death. As happens in many other examples of pathogenesis, a physiological response (increased ER stress) can led to pathology exacerbation (lack of autophagic response). If this mechanism is consistently tested in other SOD mutants as well as other ALS models, the resulting outcome could shed light upon the development of novel therapeutic approaches.

Perhaps more interestingly, and as discussed by the authors, ALS pathology shares protein aggregation with other neurodegenerative diseases, such as Alzheimer’s and many others. Is the potential protective role of XBP downregulation also applicable to those diseases? The role of XBPs as a pro-aggregator agent is also interesting. What could be the pathways implicated after XBP? Is XBP-induced ERAD upregulation instrumental in this? Results of the authors suggest that EDEM or other proteins implicated in ERAD could be novel targets of therapeutics. Thus, paradoxically, ERAD impairment would lead to enhanced clearance of misfolded proteins. This could be also related to the described protective role of protein aggregates. This is so if we consider that those aggregates, depending on their cellular location, may actually decrease the chances for XBP activation.

On the other hand, overall results show a dark side of XBP-driven responses. One wonders if viability of the cells is affected by downregulation of XBPs. It seems that it isn't in control conditions, but what about ER stress conditions? If one considers that mutant SOD leads to ER stress, and XBP downregulation enhances survival in those conditions, then XBP expression should have another important regulatory function in these cells. Otherwise, it would not have been evolutionarily advantageous to conserve this pathway. In addition to this, it is clear that XBP downregulation protects cells against nutrient starvation-induced cell death. This, when added to the lack of observable pathological phenotype of XBP downregulation in neuronal cells, strongly suggests that overall activation of UPR may not always be beneficial.

It is also interesting that glia appear not to be affected by XBP downregulation in vivo. This is puzzling, as many other researchers have stressed the importance of the neuronal-muscle-glia crosstalk in the pathogenesis of the disease. Thus, this study puts the focus on motor neuron cell biology as a major contributor to fALS.

Finally, as the authors clearly express, gender matters. As in many other diseases or physiological conditions, females seem to have natural advantages. Though it may be very speculative and naive, those results fit with the hypothesis of ALS as an accelerated aging phenomenon restricted to motor neurons: females, when compared with males of equal chronological age, exhibit decreased levels of several biomarkers of aging, finally resulting in increased lifespan. Obviously, research into the biological determinants (either chromosomal or endocrine) of gender in ALS could also open novel paths for finding a cure for this disease.

View all comments by Manuel Portero