Alzheimer's disease pathogenesis: standing at the crossroad of lipid metabolism and immune response

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by macroscopic features such as cortical atrophy, narrowing of the gyri, widening of the sulci, and enlargement of the ventricles. At the cellular level, the pathological characteristics include the extracellular aggregation of β-amyloid (Aβ) forming senile plaques, and the intracellular accumulation of hyperphosphorylated tau proteins forming neurofibrillary tangles. AD leads to the progressive decline of cognitive, behavioral, and social abilities, with no effective treatment available currently. The pathophysiology of AD is complex, involving mechanisms such as immune dysregulation and lipid metabolism alterations. Immune cells, such as microglia, can identify and clear pathological aggregates like Aβ early in the disease. However, prolonged or excessive activation of immune cells may trigger chronic neuroinflammation, thereby accelerating neuronal damage and the progression of AD. Lipid metabolism plays a critical role in maintaining cell membrane structure and function, regulating the production and clearance of Aβ, and supplying energy to the brain. Disruptions in these processes are closely linked to the pathological progression of AD. The interaction between lipid metabolism and the immune system further exacerbates the disease progression of AD. In this review, we discuss the lipid metabolism and immune response in AD, summarize their intricate interactions, and highlight the complexity of the multifactorial pathogenic cascade, offering insights into new interventions targeting the immune-metabolic axis in AD.

Keywords: Alzheimer's disease; Immune response; Immunometabolism; Lipid metabolism; Molecular mechanism.

Fig. 1

Immune response in Alzheimer’s Disease. Under the stimulation of Aβ, microglia are activated and secrete multiple inflammatory cytokines and chemokines, which trigger neuroinflammatory response. It also activates astrocytes, further exacerbating the inflammatory response. Activated T cells and B cells secrete pro-inflammatory and anti-inflammatory cytokines, regulate the state transition of microglia, as well as astrocytes and dendritic cells, and participate in the regulation of immunity and inflammation in the progression of AD. Overall, during the progression of AD, the immune response shifts from an activated and elevated state in the early stage, attempting to counteract pathological products such as Aβ, to a complex imbalanced state in the later stage. Excessive inflammatory reactions persist and mutually promote neurodegenerative changes. Meanwhile, although regulatory immune mechanisms are involved, they are difficult to restore immune balance

Fig. 2

Lipid metabolism in Alzheimer’s Disease. Lipid metabolism in AD involves cholesterol synthesis, esterification and transport, and oxidation of fatty acids. The upward arrows indicate an increase in enzyme expression/activity and associated metabolic pathways. By targeting these enzymes and transporters, such as ACAT, ABCA1, CPT, and SREBPs, which regulate lipid metabolism and affect lipid synthesis, transport, and storage, it is possible to reduce AD pathology. This could potentially slow down or mitigate the progression of Alzheimer’s disease by modulating the abnormal lipid metabolism that is associated with the disease

Fig. 3

Immunometabolism in Alzheimer’s disease. The diagram illustrates the interaction between the immune response and lipid metabolism in AD, covering complex mechanisms from the tissue level to the cellular level. The figure presents the immune system activation, inflammatory response, and how lipid metabolism affects the healthy state of nerve cells, revealing the pathological process and potential therapeutic targets in AD. Current methodologies used to study the interaction between immunity and lipid metabolism primarily include in vivo and in vitro experiments, along with bioinformatics approaches such as omics analyses. In vivo studies commonly employ transgenic or gene knockout mouse models, LPS-induced neuroinflammation models, and high-fat diet-induced models. In vitro experiments typically utilize central nervous system immune cells to investigate the crosstalk between lipid metabolism and immune responses. Omics approaches such as RNA sequencing, lipidomics, and single-cell sequencing, facilitate the identification of key regulatory networks involving inflammatory factors and lipid metabolism-related genes. Future research on the interaction between immunity and lipid metabolism in AD should focus on identifying critical molecules and signaling pathways, ultimately facilitating the construction of a more comprehensive immune–lipid metabolism interaction network in AD