Revisiting the Controversial Role of Cellular Cholesterol in Alzheimer’s Disease Pathogenesis

Alzheimer’s disease (AD) remains a complex and challenging neurodegenerative condition with far-reaching implications for public health. Extensive studies have been conducted to understand the complex mechanisms causing AD pathogenesis. One of the mechanisms that caught significant attention is the relationship between lipids, particularly cholesterol, and AD pathology. The link between lipids and AD pathology dates back more than a century when Alois Alzheimer first described the presence of “lipoid granules” in postmortem AD brain tissue as a third pathological hallmark of the disease. Many previous biological, epidemiological, and genetic studies have implicated cholesterol loss in AD pathogenesis. These studies have highlighted associations between cholesterol and key AD pathologies, including tau pathology, apoptosis, synaptic injuries, and inhibition of autophagy. However, the role of cholesterol in amyloid-β (Aβ) generation, a well-recognized feature of AD, has remained contentious. While most cell culture studies have suggested that elevated cellular cholesterol levels increase Aβ production, a few have indicated the opposite. Genetic factors have emerged as crucial contributors to AD pathogenesis, shedding light on the role of cholesterol in the disease. Susceptible genes and gene polymorphisms associated with cholesterol transport, uptake, and intracellular trafficking have been identified in the brains of hereditary AD animals and patients. These genetic alterations often lead to decreased cholesterol transport, uptake, and intracellular trafficking, resulting in cellular cholesterol deficiency or loss. Importantly, genetic data strongly support the idea that cellular cholesterol deficiency contributes to various AD pathologies, including Aβ production and deposition, tau protein accumulation, and synaptic impairment. Thus, understanding the genetic basis of cholesterol-related AD pathologies has become pivotal in exploring the role of cholesterol in Aβ metabolism.

In a recent study published in the Journal of Lipid Research by Dr. Yue Huang, Dr. Wenbin Zhang, Dr. Xiaorou Guo, Dr. Ying Zhang, Dr. Junfeng Wu, and Professor Hengbing Zu from the Jinshan Hospital Affiliated to Fudan University sheds new light on the role of cellular cholesterol in Aβ production, challenging previous notions and offering insights that may reframe our understanding of AD pathogenesis. The authors used novel neuronal and astrocytic cell models to investigate the role of cellular cholesterol in Aβ production. These models effectively regulated cellular cholesterol levels through the knockdown or knockin of the 3β-hydroxysterol-Δ24 reductase (DHCR24) gene, a key synthetase in cellular cholesterol synthesis and homeostasis. The use of these models allowed for the creation of physiological and pathological conditions closely resembling those found in AD.

The authors’ results were compelling and challenged previous beliefs regarding cholesterol’s role in Aβ generation. When cellular cholesterol levels were effectively modulated by DHCR24 knockdown, cellular cholesterol deficiency was observed. Intriguingly, this deficiency led to an increase in amyloid precursor protein (APP) processing and Aβ40/42 generation in both neuronal and astrocytic cell lines. Conversely, when cellular cholesterol levels were elevated through DHCR24 knockin, Aβ40/42 production decreased. This finding suggested that cellular cholesterol deficiency, rather than excess, promoted Aβ production. Furthermore, the researchers showed that APP overexpression, a common feature in previous cell models, disrupted cellular cholesterol homeostasis and led to increased APP β-cleavage and Aβ generation. This discrepancy between previous results and the new findings is attributed to the differences in cell models. The authors argued that the overexpression of APP in previous models disrupted cellular cholesterol homeostasis, making them less suitable for investigating cholesterol’s role in Aβ metabolism.

The research team also emphasized the potential role of astrocytes in Aβ production. Although neurons have traditionally been considered the primary source of Aβ, they found that astrocytes express APP and possess the machinery for Aβ production. Intracellular Aβ deposits were observed in activated astrocytes surrounding Aβ plaques, highlighting their contribution to Aβ pathology. Given that astrocytes are the main source of cholesterol in the brain, understanding their involvement in Aβ production may provide valuable insights into AD pathogenesis. The study extended its investigation to cholesterol-associated proteins involved in Aβ generation. It examined the expression of proteins such as Flotillin-1 and sortilin-related receptor 1 (SORL1/SorLA), which play crucial roles in vesicle trafficking and APP intracellular trafficking. The results showed that altered cellular cholesterol levels influenced the expression of these proteins, further implicating cholesterol in the regulation of APP processing and Aβ generation.

In conclusion, the recent study by Professor Hengbing Zu and colleagues challenges the conventional understanding of the role of cellular cholesterol in AD pathogenesis. It provides compelling evidence that cellular cholesterol deficiency, rather than excess, promotes Aβ production. The study highlights the importance of using appropriate cellular models and offers valuable insights into the complex interplay between cholesterol, APP processing, and Aβ generation. Moreover, it is noteworthy the potential involvement of astrocytes in Aβ production and the significance of cholesterol-associated proteins in AD pathology. This research prompts a reevaluation of previous findings and opens new avenues for understanding and targeting the underlying mechanisms of Alzheimer’s disease.