Chaperone-Mediated Responses and Mitochondrial–Endoplasmic Reticulum Coupling: Emerging Insight into Alzheimer’s Disease
Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is t...
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2025-07-01
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| author | Manish Kumar Singh Minghao Fu Sunhee Han Jyotsna S. Ranbhise Wonchae Choe Sung Soo Kim Insug Kang |
| author_facet | Manish Kumar Singh Minghao Fu Sunhee Han Jyotsna S. Ranbhise Wonchae Choe Sung Soo Kim Insug Kang |
| author_sort | Manish Kumar Singh |
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| description | Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders. |
| format | Article |
| id | doaj-art-a1514675b7e34c34bb848bd5a14ea9f9 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-07-01 |
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| series | Cells |
| spelling | doaj-art-a1514675b7e34c34bb848bd5a14ea9f92025-08-20T04:00:54ZengMDPI AGCells2073-44092025-07-011415117910.3390/cells14151179Chaperone-Mediated Responses and Mitochondrial–Endoplasmic Reticulum Coupling: Emerging Insight into Alzheimer’s DiseaseManish Kumar Singh0Minghao Fu1Sunhee Han2Jyotsna S. Ranbhise3Wonchae Choe4Sung Soo Kim5Insug Kang6Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of KoreaDepartment of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of KoreaDepartment of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of KoreaDepartment of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of KoreaDepartment of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of KoreaDepartment of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of KoreaDepartment of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of KoreaAlzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders.https://www.mdpi.com/2073-4409/14/15/1179Alzheimer’s diseaseamyloid-βaggregatescalciumchaperonesendoplasmic reticulum |
| spellingShingle | Manish Kumar Singh Minghao Fu Sunhee Han Jyotsna S. Ranbhise Wonchae Choe Sung Soo Kim Insug Kang Chaperone-Mediated Responses and Mitochondrial–Endoplasmic Reticulum Coupling: Emerging Insight into Alzheimer’s Disease Cells Alzheimer’s disease amyloid-β aggregates calcium chaperones endoplasmic reticulum |
| title | Chaperone-Mediated Responses and Mitochondrial–Endoplasmic Reticulum Coupling: Emerging Insight into Alzheimer’s Disease |
| title_full | Chaperone-Mediated Responses and Mitochondrial–Endoplasmic Reticulum Coupling: Emerging Insight into Alzheimer’s Disease |
| title_fullStr | Chaperone-Mediated Responses and Mitochondrial–Endoplasmic Reticulum Coupling: Emerging Insight into Alzheimer’s Disease |
| title_full_unstemmed | Chaperone-Mediated Responses and Mitochondrial–Endoplasmic Reticulum Coupling: Emerging Insight into Alzheimer’s Disease |
| title_short | Chaperone-Mediated Responses and Mitochondrial–Endoplasmic Reticulum Coupling: Emerging Insight into Alzheimer’s Disease |
| title_sort | chaperone mediated responses and mitochondrial endoplasmic reticulum coupling emerging insight into alzheimer s disease |
| topic | Alzheimer’s disease amyloid-β aggregates calcium chaperones endoplasmic reticulum |
| url | https://www.mdpi.com/2073-4409/14/15/1179 |
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