When it works properly, the endoplasmic reticulum (ER) constantly pumps out newly synthesized membrane proteins, perfectly folded and sorted to their proper cellular destination. At the same time, this organelle keeps cellular calcium levels in balance. But when the ER gets overloaded and stressed, the cell counters with the unfolded protein response (UPR), a pathway which results in slowed protein synthesis and enhanced chaperone production to clear the backlog. If the overload persists, as it does in many neurodegenerative diseases featuring continuous production of mutant, malshaped proteins, such as Alzheimer disease (AD), cells undergo an ER-dependent form of apoptosis (see ARF related news story).

But ER stress can also come from without, according to new work from Claudia Pereira and colleagues at the University of Coimbra in Portugal. In a paper published online July 14 in the Neurobiology of Disease, the researchers report that application of Aβ1-40 to cultured neurons causes ER stress via pathological release of intracellular calcium stores. Chronically elevated intracellular calcium then leads to oxidative stress and cytochrome c release from mitochondria, triggering caspase activation and cell death. Blocking calcium release by inhibiting ER calcium channels reverses all these effects of Aβ and rescues neurons. Their results show that ER stress, induced by Aβ added to cells, can cooperate with mitochondrial pathways to trigger cell death. The results may apply to other diseases, too, since they showed that a neurotoxic prion peptide had very similar effects.

In other news from the ER, a study from Malcolm Horne and colleagues at the University of Melbourne in Australia shows upregulation of the UPR in SOD mutant models of ALS, and suggests that increased chaperone levels may be neuroprotective. Lastly, some basic research on the UPR reminds us once again how elegantly evolution solves life and death problems like protecting ER function. Work from Jonathan Weissman’s lab at the University of California, San Francisco, reveals a third arm to the UPR—in addition to transcriptional and translational responses, the cell also initiates degradation of mRNAs that specifically code for ER-targeted proteins.

Studies on the role of ER stress in Alzheimer disease have focused mostly on the presenilin proteins (PS). FAD-causing PS mutations interfere with protein folding and sensitize cells to ER stress-induced cell death by downregulating the UPR (see ARF related news story). But there have been hints that the ER stress-induced apoptosis could be involved in Aβ toxicity. Work from Junying Yuan’s lab at Harvard University showed that neurons from caspase-12 knockout mice were resistant to ER stress-induced cell death, and also Aβ toxicity (see ARF related news story). Soluble amyloid oligomers perturb calcium homeostasis in neurons, which is another trigger of ER stress (De Muro et al., 2005).

For these reasons, Pereira’s group looked specifically for ER-mediated apoptosis in response to exogenous Aβ1-40 peptides in cultured cortical neurons. First author Elisabete Ferreiro and colleagues showed that Aβ treatment increased ER stress, as indicated by elevated protein levels of the chaperone Grp78 and caspase-12 activation. Aβ also caused a rapid (within 1 hour) and sustained (up to 48 hours) increase in intracellular calcium. The calcium was derived from ER stores, since its accumulation was blocked by inhibiting either of the two major ER calcium release channels, the ryanodine receptor (RyR) and the inositol trisphosphate receptor (IP3R), with dantrolene or xestospongin C, respectively.

High intracellular calcium can stress out mitochondria, too, and the researchers showed that Aβ caused oxidative stress and apoptosis via a mitochondrial pathway. They recorded elevated production of reactive oxygen species, cytochrome c release from mitochondria, caspase activation (including the executioner caspase, caspase-3), and cell death. All these effects were inhibited by danotrolene or xestospongin C. From this data, the authors conclude that Aβ causes significant, early release of intracellular calcium, ER stress, and activation of the mitochondrial apoptosis pathway. Their results raise the possibility that calcium release channel blockers might be useful to protect against neuron loss in AD and prion diseases.

The UPR and ER stress-induced apoptosis also figure in the death of motor neurons triggered by mutant superoxide dismutase in ALS, according to the Australian researchers. In their paper, published online July 17 in the JBC, first author Julie Atkin and coworkers show that SOD1 mutant mice upregulate several markers of the UPR, including cleaved caspases-12, -9, and -3. They also found that the ER chaperone protein disulfide isomerase (PDI) was upregulated and associated with mutant SOD1 in rodent ALS models and in cells. Inhibiting PDI increased SOD1 aggregation, suggesting that the increased PDI they observed might represent a neuroprotective response. This report jibes with a paper earlier this year from Stuart Lipton, Eliezer Masliah, and Yasuyuki Normura describing inactivation of PDI in brains of AD and PD patients and suggesting that loss of PDI activity could exacerbate the pathology of neurodegenerative diseases (see ARF related news story).

And finally, a fascinating paper in the July 7 issue of Science shows that there is more to the UPR than upregulation of chaperones. The two major effector arms of the UPR both emanate from the ER transmembrane protein IRE-1. Sensing a build-up of unfolded proteins on its luminal side, IRE-1 activates cytosolic kinase and ribonuclease activities, which upregulate chaperone production (through RNA splicing to produce transcription factors) and downregulate protein synthesis at the level of translation. The net effect is to enhance the capacity of the ER while reducing its load. Now, Julie Hollien and Jonathan S. Weissman reveal that IRE-1 activation also leads to a rapid and specific degradation of mRNAs targeted to the ER. Using its cytosolic ribonuclease activity, IRE-1 chews up the mRNAs for the nascent polypeptides it senses in the lumen of the ER. This targeted destruction gives the ER an immediate time-out from protein folding, and also allows it to accommodate the increased syntheses of chaperones that comes later in the UPR. The elegant logic of the UPR thus revealed should only increase our appreciation of and curiosity about the role of this critical homeostatic mechanism in the health and demise of neurons.—Pat McCaffrey


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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.

  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.


    . The unfolded protein response is activated in Alzheimer's disease. Acta Neuropathol. 2005 Aug;110(2):165-72. PubMed.

    . Protein quality control in Alzheimer's disease: a fatal saviour. Curr Drug Targets CNS Neurol Disord. 2005 Jun;4(3):283-92. PubMed.

  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.


    . 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. PubMed.

  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.


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

    . 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 Jul;16(2):417-27. PubMed.

    . Lithium inhibits Abeta-induced stress in endoplasmic reticulum of rabbit hippocampus but does not prevent oxidative damage and tau phosphorylation. J Neurosci Res. 2003 Mar 15;71(6):853-62. PubMed.

  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.


News Citations

  1. Move Over, Mitochondria—Make Room for ER-Induced Cell Death
  2. Presenilin-1 Interferes with Protein Folding
  3. Death Takes a Different Cell Route
  4. NO Laughing Matter—Nitrosylation of Isomerase Spells Trouble for Neurons

Paper Citations

  1. . Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem. 2005 Apr 29;280(17):17294-300. PubMed.

Further Reading


  1. . ER stress and neurodegenerative diseases. Cell Death Differ. 2006 Mar;13(3):385-92. PubMed.
  2. . The unfolded protein response is activated in Alzheimer's disease. Acta Neuropathol. 2005 Aug;110(2):165-72. PubMed.
  3. . Disturbed activation of endoplasmic reticulum stress transducers by familial Alzheimer's disease-linked presenilin-1 mutations. J Biol Chem. 2001 Nov 16;276(46):43446-54. PubMed.
  4. . Neurons overexpressing mutant presenilin-1 are more sensitive to apoptosis induced by endoplasmic reticulum-Golgi stress. J Neurosci Res. 2002 Aug 15;69(4):530-9. PubMed.
  5. . Induction of neuronal death by ER stress in Alzheimer's disease. J Chem Neuroanat. 2004 Sep;28(1-2):67-78. PubMed.
  6. . Increased production of beta-amyloid and vulnerability to endoplasmic reticulum stress by an aberrant spliced form of presenilin 2. J Biol Chem. 2001 Jan 19;276(3):2108-14. PubMed.

Primary Papers

  1. . An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiol Dis. 2006 Sep;23(3):669-78. PubMed.
  2. . Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science. 2006 Jul 7;313(5783):104-7. PubMed.
  3. . Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J Biol Chem. 2006 Oct 6;281(40):30152-65. PubMed.