Role of Endoplasmic Reticulum Stress in Learning and Memory Impairment and Alzheimer's Disease-Like Neuropathology in the PS19 and APPSweMouse Models of Tauopathy and Amyloidosis
Open accessAbstract
Emerging evidence suggests that endoplasmic reticulum (ER) stress may be involved in the pathogenesis of Alzheimer’s disease (AD). Recently, pharmacological modulation of the eukaryotic translation initiation factor-2 (eIF2α) pathway was achieved using an integrated stress response inhibitor (ISRIB). While members of this signaling cascade have been suggested as potential therapeutic targets for neurodegeneration, the biological significance of this pathway has not been comprehensively assessed in animal models of AD. The present study investigated the ER stress pathway and its long-term modulation utilizing in vitro and in vivo experimental models of tauopathy (MAPT P301S)PS19 and amyloidosis (APP Swe). We report that thapsigargin induces activating transcription factor-4 (ATF4) in primary cortical neurons (PCNs) derived from rat and APP Swe nontransgenic (nTg) and transgenic (Tg) mice. ISRIB mitigated the induction of ATF4 in PCNs generated from wild-type (WT) but not APP Swe mice despite partially restoring thapsigargin-induced translational repression in nTg PCNs.In vivo, C57BL/6J and PS19 mice received prolonged, once-daily administration of ISRIB. While the compound was well tolerated by PS19 and C57BL/6J mice, APP Swe mice treated per this schedule displayed significant mortality. Thus, the dose was reduced and administered only on behavioral test days. ISRIB did not improve learning and memory function in APP Swe Tg mice. While ISRIB did not reduce tau-related neuropathology in PS19 Tg mice, no evidence of ER stress-related dysfunction was observed in either of these Tg models. Taken together, the significance of ER stress and the relevance of these models to the etiology of AD require further investigation.
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In PS19 mice, there were no robust differences in spine density when PS19 mice were compared to NTG littermates, despite reported behavioral and electrophysiological deficits at the ages assessed.
“Although behavioral and electrophysiological deficits have been reported in the PS19 line at the ages assessed in our study (Yoshiyama et al., 2007, Takeuchi et al., 2011, Briggs et al., 2017, Chalermpalanupap et al., 2018), we did not observe robust differences in spine density when PS19 mice were compared to NTG littermates.”
From Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice (2021) · cites this paper as Briggs et al., 2017
The Results section reports behavioral differences between PS19 and nontransgenic mice, including locomotor hyperactivity and spatial learning and memory deficits; Materials and Methods identifies the PS19 mice as 8–9 months old (page numbers unavailable). The cited paper does not report electrophysiological deficits in PS19 mice. The spine-density finding is the citing authors’ own result, not a finding attributed to this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredm6A accumulates in the cytoplasm in response to stress.
“m6A is known to accumulate in the cytoplasm in response to stress, but the function of cytoplasmic m6A remains to be clearly delineated (Meier et al., 2016; Briggs et al., 2017; Koren et al., 2019; Ries et al., 2019; Wolozin and Ivanov, 2019; Fu and Zhuang, 2020).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as Briggs et al., 2017
The Introduction discusses ER stress, unfolded proteins, and stress-related translation of ATF4 mRNA, but not m6A or its location in the cell. Searches for m6A, cytoplasmic accumulation, and N6-methyladenosine found no passage in our copy addressing the claim. (LLM, conf=0.76)
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- Authors
- Briggs, D. I., Defensor, E., Memar Ardestani, P., Yi, B., Halpain, M., Seabrook, G., & Shamloo, M.
- Affiliations
- Stanford Medicine (US)
- Johnson & Johnson (United States) (US)
- Corresponding author
- Shamloo, Mehrdad
- Venue
- eneuro
- Publisher
- Society for Neuroscience
- Published
- 2017-07
- Volume
- 4
- Issue
- 4
- Pages
- ENEURO.0025-17.2017
- ISSN
- 2373-2822 (ISSN-L)
- PMC
- PMC5510086
- OpenAlex
- W2733899114
- Cited by
- 61
- References
- 73
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 10 · 2023: 5 · 2022: 7 · 2021: 7 · 2020: 12 · 2019: 5 · 2018: 6 · 2017: 1
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- eNeuro (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Johnson & Johnson (Innovation Grant)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- endoplasmic reticulum stress, Alzheimer's disease, integrated stress response, ISRIB, ATF4, thapsigargin, tauopathy, PS19 mice, amyloidosis, learning and memory impairment, cortical neurons, protein synthesis inhibition, neurodegeneration
- MeSH terms
- Acetamides, Alzheimer Disease, Amyloidosis, Animals, Cells, Cultured, Cerebral Cortex, Cyclohexylamines, Disease Models, Animal, Hippocampus, Learning, Learning Disabilities, Male, Memory, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Rats, Sprague-Dawley, Neuroprotective Agents, Thapsigargin, Endoplasmic Reticulum Stress
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