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Oliveira MM, Lourenco MV, Longo F, Kasica NP, Yang W, Ureta G, Ferreira DD, Mendonça PH, Bernales S, Ma T, De Felice FG, Klann E, Ferreira ST. Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer's disease. Sci Signal. 2021 Feb 2;14(668) PubMed.
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University of Michigan
This paper provides additional data for the integrated stress response (ISR) as playing an active role in models of neurodegenerative disease. This response pathway both impacts protein synthesis and leads to stress-granule formation. Prior studies suggest this stress response is chronically activated in animal models and patients with ALS and prion disorders. Moreover, ISR pathways are important in synaptic function and plasticity.
Here, Oliviera and colleagues demonstrate that ISRIB, which interrupts this stress-response pathway and precludes its shutdown of protein synthesis, improves phenotypes in two models of Alzheimer’s disease. Perhaps most interesting is the corrections observed in synaptic function in these models.
While valuable, it is important to note that these studies were both performed in overexpression model systems, which may overrepresent the importance of these pathways in AD disease pathogenesis. As such, further studies validating these findings will be needed to fully interpret the role of this pathway in AD.
View all comments by Peter ToddUCSF
UCSF
Targeting Protein Synthesis Translational Control to Treat Dementia.
Memory disorders pose a major threat to public health and are responsible for an enormous economic and social burden. Long-term memory formation diminishes with normal aging and among many clinical conditions, including brain injury, and neurodegenerative diseases. The integrated stress response (ISR)—a cell-intrinsic translation regulatory network—constitutes the underlying pathway of cognitive dysfunction in numerous disorders.
Indeed, activation of the ISR impairs long-term memory formation. The ISR is a conserved intracellular signaling pathway that serves as a universal protein synthesis regulator for the eukaryotic initiation factor eIF2 (eIF2α), via the guanine nucleotide exchange factor (eIF2β). Increased phosphorylation of eIF2α (eIF2α-P) halts global protein synthesis and reprograms translational upregulation of a select subset of mRNAs. ISR activation is detected in postmortem brains from individuals with, and animal models of, Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury, and Down’s syndrome. At preclinical level, cognitive deficits in mouse models of Alzheimer’s disease, traumatic brain injury, and aging result from ISR activation. Notably, a small molecule that inhibits the integrated stress response (ISRIB) stabilizes eIF2β even in the presence of eIF2α-P, thus restoring global protein synthesis. Targeting the ISR, and specifically eIF2β activity via ISRIB, represents a compelling approach to restore memory consolidation in numerous pathological conditions.
In this study Oliveira and colleagues analyzed postmortem brain tissues from Alzheimer’s disease patients and found increases in eIF2α-P and decreases in eIF2β protein levels. These findings strengthen the idea that targeting the ISR may be an effective therapeutic strategy to ameliorate AD-associated memory deficits.
Next, the authors used two different mouse models of AD (acute injections of Aβ oligomers and mice carrying the APP Swedish mutation characterized by age dependent accumulation of Aβ [APPswe/PS1∆E9 mice]). Systemic low-dose injections of ISRIB over several days rescued measures of synaptic function and memory deficits. Interestingly, while the treatment reduced Aβ plaque size, it also resulted in an increase in plaque density. These results suggest that while ISR interference directly affects neuronal function (measured by LTP, dendritic spine density, and memory measures), it also modulates Aβ pathology. While the results are promising, further investigations are needed to understand the downstream molecular mechanisms by which ISR activation modulates AD pathophysiology, specifically Aβ plaques and tau pathology, the other key component of AD.
Converging evidence suggests that the ISR may be a central molecular switch for memory consolidation, applicable to a wide range of neurodegenerative disorders and diseases, brain injury, and aging (image below). Inhibition of the ISR has been shown to reverse cognitive and synaptic deficits induced by traumatic brain injury, aging, and Down’s syndrome (Chou et al., 2017; Krukowski et al., 2020; Krukowski et al., 2020; Zhu, 2019). ISRIB shows no overt toxicity in mice and promises to become a powerful treatment for cognitive dysfunction.
Fig. 1 from Costa-Mattioli and Walter, Science 368:eaat5314, Review 2020.
Since the discovery of ISRIB in 2013 at the University of California, San Francisco, by the Walter lab, the drug has been licensed to Calico, which recently announced with Abbvie its use in clinical trials. Specifically, its lead elF2β activator, ABBV-CLS-7262, is currently progressing through Phase 1 with the plan to begin a trial later this year in patients with ALS (press release).
Alzheimer’s disease was first described in the early 1900s and so far, current treatments have only been able to partially address AD-associated symptoms. While ISRIB may or not be a cure for AD, it is promising that targeting a pathway shared by many pathological conditions could greatly advance pharmacological treatments for dementia.
References:
Costa-Mattioli M, Walter P. The integrated stress response: From mechanism to disease. Science. 2020 Apr 24;368(6489) PubMed.
Krukowski K, Nolan A, Frias ES, Boone M, Ureta G, Grue K, Paladini MS, Elizarraras E, Delgado L, Bernales S, Walter P, Rosi S. Small molecule cognitive enhancer reverses age-related memory decline in mice. Elife. 2020 Dec 1;9 PubMed.
Krukowski K, Nolan A, Frias ES, Grue K, Becker M, Ureta G, Delgado L, Bernales S, Sohal VS, Walter P, Rosi S. Integrated Stress Response Inhibitor Reverses Sex-Dependent Behavioral and Cell-Specific Deficits after Mild Repetitive Head Trauma. J Neurotrauma. 2020 Jun 1;37(11):1370-1380. Epub 2020 Feb 11 PubMed.
Chou A, Krukowski K, Jopson T, Zhu PJ, Costa-Mattioli M, Walter P, Rosi S. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):E6420-E6426. Epub 2017 Jul 10 PubMed.
Rabouw HH, Langereis MA, Anand AA, Visser LJ, de Groot RJ, Walter P, van Kuppeveld FJ. Small molecule ISRIB suppresses the integrated stress response within a defined window of activation. Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2097-2102. Epub 2019 Jan 23 PubMed.
Zhu PJ, Khatiwada S, Cui Y, Reineke LC, Dooling SW, Kim JJ, Li W, Walter P, Costa-Mattioli M. Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome. Science. 2019 Nov 15;366(6467):843-849. PubMed.
View all comments by Elma FriasUniversity of Cambridge and UK Dementia Research Institute
This paper from Oliveira et al. shows exciting data in AD mouse models that add to the growing body of evidence for repressed protein synthesis rates contributing to memory failure and neuronal loss in neurodegenerative diseases. Critically, it further builds confidence in dysregulated proteostasis as a drug target for the treatment of these disorders. Reduced translational rates are seen in the brain across the range of mouse models of neurodegenerative diseases, from Parkinson’s to prion to ALS and frontotemporal dementia, associated with overactivation of the Unfolded Protein Response (UPR), particularly the PERK branch. The resultant high levels of PERK-P and its downstream target eIF2α-P lead to repression of translation (protein synthesis rates) that starves synapses of essential proteins and leads to synapse loss and eventually neurodegeneration.
Earlier data from the authors had shown the effects of genetically restoring protein synthesis by targeting PERK or eIF2α kinases in the related integrated stress response (ISR) in AD mice, backed up by genetic and pharmacological targeting of PERK in various mouse models. ISRIB and molecules targeting the pathway downstream of eIF2α-P, such as the repurposed drug trazodone, have been particularly exciting due to lack of toxic side effects (both on- and off-target) seen with PERK inhibitors that limited enthusiasm for UPR inhibition as a therapeutic strategy.
Previous work has shown that the small molecule ISRIB restores translation and memory in Down’s syndrome, prion disease, traumatic brain injury and in aged mice, but data from AD models was controversial—likely due to dosing regimens. Here, Oliviera and colleagues show that regular dosing with ISRIB at lower levels restores protein synthesis, memory, and synaptic plasticity in different mouse models of AD—both transgenic APP/PS1 mice and Aβ oligomer treated wild-type mice. The brains of patients with these disorders, notably Alzheimer’s disease and tauopathies, show high levels of PERK-P and eIF2α-P and Oliviera further found reduced levels of eIF2β subunits in patients’ brains and a key component of the translational apparatus and “target” of eIF2α-P.
It will be fascinating to see if patients with AD, like the mouse models, have reduced protein synthesis rates due to high eIF2α-P levels, as suggested both by histological findings and by the western blotting data from Oliviera. Then, the use of ISRIB-like molecules, or repurposed drugs such as trazodone, which act in a similar manner, would be predicted to restore crucial protein synthesis rates in patient brains, boosting memory and neuronal survival. Oliviera and colleagues’ elegant paper further increases confidence in targeting this pathway for treatment of Alzheimer’s and related disorders.
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