Neurolipid systems: A new target for the treatment of dementia

Dementia is a nonspecific brain disorder characterized by a set of common signs and symptoms that frequently appears after brain damage caused by injury or disease and is heavily related to aging. Along with neurodegenerative signs and neurological symptoms, such as impairments in progressive learning and memory, other symptoms are usually observed related to difficulties in behavioural, motor or emotional aspects, including language problems and depression. These signs may vary based on the type of dementia and the characteristics of each patient, which generates a large and heterogeneous group of different clinical profiles requiring individualized treatments.¹ Several neurodegenerative disorders are accompanied by different symptoms of dementia, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Currently, there are few effective pharmacological treatments indicated for these diseases, and they are generally focused on symptomatic relief rather than targeting the neurodegenerative process. Moreover, there is a lack of early diagnostic biomarkers for early detection.

AD, the most common dementia worldwide, is characterized by a progressive cognitive impairment of learning and memory, with fatal consequences for the patient. While the classical histopathological hallmarks of AD include extracellular amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein, synaptic loss is the parameter that best correlates with disease progression.² Neurotransmitter systems specifically affected in AD include cholinergic pathways and also lipid-based neurotransmitter systems such as the endocannabinoid (eCB).³ Currently, the only approved treatments for the disease are inhibitors of acetylcholinesterase, antagonists of NMDA receptors, and more recently, anti-amyloid-β peptide antibodies; the last one is not exempt from controversy, and all of them show very limited improvements.

PD is principally a motor disorder that often courses with cognitive impairment. Recently, some types of PD have been defined neuropathologically as an alpha synucleinopathy showing accumulation of alpha synuclein protein in dopaminergic neurons of the substantia nigra that may lead to neuronal death and progressive impairment of the motor cognition of the patient. PD patients can develop a specific type of dementia, which is characterized by cognitive impairment, visual hallucinations and, more importantly, parkinsonism, defined by bradykinesia, gait impairment and rest tremor, among other symptoms.⁴ As is the case with other neurodegenerative diseases, it has no healing treatment, being L-Dopa the most effective drug to mitigate the motor symptoms.

Unlike AD and PD, HD is a hereditary neurodegenerative disease, being the most common form of genetic-associated dementia. It is caused by a cytosine-adenine-guanine (CAG) trinucleotide repetition in the gene that encodes the huntingtin protein on chromosome 4.⁵ Chorea, characterized by brief, semi-directed and irregular movements, is the most characteristic symptom of HD, and the treatment lies in antipsychotics and benzodiazepines, which do not reverse nor protect the patient from neurodegeneration.⁶

Therefore, new and innovative treatments are necessary for these three neurodegenerative diseases.

Lipids are widely recognized for their roles in providing structure, energy storage and thermoregulation to the organism. However, it is important to broaden our perspective on lipids, as some of them also possess signalling capabilities in the CNS through binding and activation to G protein-coupled receptors (GPCRs).⁷ There is a large variety of lipids in the CNS classified according to their chemical structures, such as sphingolipids, phospholipids, cholesterol and glycosphingolipids.⁸ Few of them can be considered integral members of the extensive family of neurotransmitters and/or neuromodulators. Since peptides with these properties are called ‘neuropeptides’, lipids could be named as ‘neurolipids’.⁹ The discovery of new lipid-based neurotransmitter systems, such as eCBs, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), shifts the focus to the relevance of these systems in both neurophysiological status and neurological disorders.

Neurolipids are typically synthesized in a calcium-dependent manner, as needed. This synthesis occurs through the enzymatic processing from membrane lipid precursors by phospholipases, sphingomyelinases or cytochrome P450 hydroxylases.¹⁰ Precursors are located mainly at the cell membranes of the pre- or post-synaptic compartments. Endogenous ligands for neurolipids have the capability to interact with their respective receptors either in an autocrine manner, where they directly engage with their specific receptor within the lipid bilayer, or in a paracrine way. Their amphipathic properties allow them to easily cross the lipid bilayer, allowing them to function also in the cytoplasm¹¹ (Figure 1). Regarding their physiological roles, neurolipids have been involved in multiple processes in both peripheral and central nervous systems (CNSs), as well as regulating immune responses. These neurolipid systems are also regulated during the abovementioned neurodegenerative diseases. Thus, receptors and enzymes involved in the synthesis and degradation of the endogenous neurotransmitters of these systems could be used not only as biomarkers for early diagnosis of the mentioned diseases but also as therapeutic targets.¹²

Therefore, we have reviewed three of the most studied lipid-based or neurolipid neurotransmitter systems, namely, eCB, LPA and S1P systems, and their roles in the context of dementia linked to AD, PD and HD (Table 1, Figure 2).

Neurolipids are important signalling molecules with potential therapeutic effects against the most common dementias associated with the main neurodegenerative diseases, as has been demonstrated not only with preclinical in vitro and in vivo experiments but also with data from patients (Table 1). eCB and S1P drugs have shown relevant and interesting results in several animal models of dementias from different origins, paving the way for clinical trials, although further data acquisition is needed in this regard. Despite the limited evidence regarding the involvement of LPA, it also plays an important role in the development of dementia and could be a potential coadjutant for future therapeutic approaches.

In summary, neurolipids represent a novel approach for the advancement of innovative therapies targeting the most prevalent forms of dementia, including AD, PD and HD. A deeper comprehension of these lipid systems holds the promise of enhancing our understanding of the aetiology, progression and potential treatments for these neurological conditions.

The present review focuses on the description of the relationship of neurolipid systems in three specific diseases with dementia, such as AD, PD and HD. Among all the diseases that lead to dementia, these three are those that have attracted the most interest in the field of neurolipids. Although research on lipids that have neurotransmitter activity is a field that is expanding thanks to new techniques in the field of lipids that have been developed in recent years, there are currently not a large number of specific studies in the context of dementias, which may hinder a complete and thorough view of the subject. Much of the research in this field is conducted in animal models, limiting the direct extrapolation to human pathophysiology and its clinical relevance in dementias. A high heterogeneity has been observed in the design of the studies used for this review, and this may complicate the comparison and summarizing of the results, preventing a consensus on the usefulness of neurolipid treatments in these diseases. Due to the exponential growth of knowledge in this field, it is challenging to include every new publication within this article. Consequently, we have selectively included a limited number of the most pertinent, recent and innovative studies.

The authors have no conflicts of interest to declare.