Neuroinflammation in Parkinson’s Disease: Role of cholesterol
Dr. Patricia García Sanz
Cajal Institute, CSIC, Madrid
DOI: https://doi.org/10.35466/RA2021n6390
Keywords: Neurodegeneration, Neuroinflammation, Cholesterol, Inflamaraft, β-glucocerebrosidase, Microglia
Abstract
Parkinson's disease (PD) is the most prevalent neurodegenerative movement disorders, where dopaminergic neurons in the Substantia Nigra (SNpc) are lost, resulting in a decrease in striatal dopamine and, subsequently, motor control failure and diagnostic symptoms of resting tremor, bradykinesia and muscle rigidity. Additionally, about 40% of PD patients display depression and anxiety, as a complex mental condition that worsens their prognosis and quality of life. These non-motor symptoms and others may appear at early phases (prodromal stages) as well as during the progression of the disease (advanced stages). Dopaminergic degeneration is associated with the appearance of Lewy bodies, which contain membrane structures and misfolded proteins such as α-synuclein (α-Syn). PD is a multifactorial pathology and the main risk factors are environmental factors, genetic susceptibility and age. The number of PD patients is increasing dramatically, and so is the corresponding social and economic burden. Nearly 85-90% of PD cases are sporadic, 10-15% are family cases and 5% have Mendelian inheritance.
The central nervous system (CNS) can initiate an immune response against pathogens or endogenous danger signals, that is, it is immunocompetent. In addition, it can interact with the peripheral immune system, through the synthesis and release of neurotransmitters that can regulate the differentiation and functioning of both innate immunity cells and acquired immunity. In this way, the CNS can modulate the immune response and limit inflammation-induced tissue damage. Neuroinflammation is a complex integration of the responses of all cells present within the CNS, including the neurons, macroglia, microglia and the infiltrating leukocytes and is part of this innate immune response. It is initiated by the microglia, the macrophages of the CNS, which can be activated by various stimuli and in which astrocytes also participate. The entire inflammatory reaction must stop in order to maintain the structure and tissue homeostasis, including the removal of pathogens, dead cells, or other cellular debris, and the restoration of the tissue. If the insult persists or the mechanisms involved in terminating the inflammation are inadequate, chronic inflammation may arise. Furthermore, inflammation can also occur in response to molecules secreted by degenerating neurons, a condition called neuroinflammation, a crucial factor in neurodegenerative diseases. Neurodegenerative diseases are a heterogeneous group of CNS disorders whose etiology is still unknown. Although the molecular and cellular bases underlying these diseases are different, the final pathway in which several of these molecular or cellular events (oxidative stress, misfolded proteins, deficit of trophic factors, alteration of autophagy-lysosomal pathways, among others) in which they converge may be common (neuroinflammation), contributing over time to neuronal death through the activation of microglial populations in specific regions of brain
The presence of gliosis is a relevant pathological feature in PD. In vivo imaging studies using PET show that PD patients have a significant increase in neuroinflammation markers in the bridge region, basal ganglia, striatum, and frontal and temporal cortex, compared to controls of the same age. While post-mortem immunohistological analyzes, in the brains of PD patients, reveal morphological changes in the microglia and overexpression of pro-inflammatory proteins such as HLA-DR, COX (cyclooxygenase) and iNOS (inducible nitric oxide synthase). These data have contributed to strengthen the idea that microglial activation can occur in the early stages of the disease. These cells can induce significant neurotoxic effects due to the excess production of cytotoxic factors such as interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and nitric oxide (NO). α-Syn may play a role in the microglial activation observed in SNpc and in the increase in the expression of MHC-II molecules.
Mutations in the GBA1 gene are one of the main genetic risk factors for PD. This gene encodes an essential lysosomal enzyme called β-glucocerebrosidase (GCase), which breaks down the glycolipid glucocerebroside into glucose and ceramide. The reduced activity of GCase result in an increase in the amount of α-Syn, promoting its aggregation. These results have also been found in the brains of patients with sporadic PD. The concept of inflammarafts has recently been introduced, which are cholesterol-enriched lipid domains that are thought to act as platform mediating the cellular inflammatory response, possibly being controlled by cholesterol and sphingolipid metabolism and Apolipoprotein E. The ApoE / Cholesterol complex from astrocytes could bind to the TREM2 and TLR4 receptor on the inflamaraft surface of the microglia to trigger inflammation and phagocytosis. In the PD context, an alteration of the intracellular cholesterol content as occurs when a GCase deficiency occurs could induce a neuroinflammatory response in the microglia and astrocytes. These can be activated by the neurons' own oxidative stress or by added α-Syn secreted by these neurons, which can be transferred to the microglia and astrocytes, thus triggering the inflammatory response as well. Moreover, it has been seen that this alteration in cholesterol favors the α-Syn aggregation in lipid rafts, favoring its aggregation and altering the signaling through the TMR2 and TRL4 receptors. Therefore, it is suggested that, as a consequence of these mechanisms, GBA1 mutations ultimately increase interleukins and the NLRP3 inflammasome, activating the inflammatory response.