Chaperone-Mediated Responses and Mitochondrial-Endoplasmic Reticulum Coupling: Emerging Insight into Alzheimer's Disease

Abstract

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.

Keywords: Alzheimer’s disease; aggregates; amyloid-β; calcium; chaperones; endoplasmic reticulum; mitochondria.

Figure 1

The image illustrates multiple interconnected biological processes that contribute to the progression of Alzheimer’s disease. Key factors involved include oxidative stress (ROS), protein misfolding and unfolding, dysfunction between mitochondria and ER, as well as age-related cellular changes. Together, these processes lead to neuronal damage and cognitive decline in AD.

Figure 2

The image illustrates the interactions between ER and mitochondria under AD conditions. Mitochondrial–ER contact sites (MERCS) play a crucial role in regulating various cellular processes, including ER stress, the unfolded protein response (UPR), and protein degradation pathways such as the ubiquitin–proteasome system (UPS), autophagy, and apoptosis. Notably, MERCS are involved in ER–mitochondrial calcium (Ca²⁺) signaling through the mitochondrial calcium uniporter (MCU), and they influence the transcription of genes associated with AD risk as well as the processing of APP. Changes in the coupling between the ER and mitochondria observed in AD disrupt these processes, underscoring their significance in the progression of disease. In the diagram, the symbol () indicates the expression of upregulated proteins, () denotes inhibitory activity, and () represent the dynamics of Ca²⁺ ions within the pathways associated with ER and mitochondria.

Figure 3

This schematic illustrates the roles of the ER and mitochondria in AD. Both organelles become primary targets under various cellular stress conditions. In AD, oxidative stress and ER stress disrupt the interaction between the ER and mitochondria, which impairs crucial pathways such as the regulation of ROS, ERAD, and UPRs. Targeting these pathways therapeutically, especially through the use of natural compounds and antioxidants, may help to improve cellular dysfunctions related to AD, particularly in early stages of the disease. The symbols () indicate the expression of upregulated proteins, () denotes inhibitory activity of the compounds.