Altered immunity may have destructive consequences for the integrated central nervous system. This immune response often affects progressive neurodegenerative diseases such as Parkinson’s disease and/or psychiatric disorders such as schizophrenia. In particular, schizophrenia pathogenesis may be mediated by multiple neuro-immune interaction pathways. Gut microbiota might affect the brain and/or immune function. Significant machineries of immunity are commonly affected by the commensal gut microbiota. Therefore, schizophrenia may be connected with the gut-immune system. In addition, the brain and immune systems cooperate on multiple levels. The brain could save several pieces of information about specific inflammation in a body. This immunological memory named “engrams”, also called memory traces, could restore the initial disease state, which may help to explain key features of schizophrenia. Based on this concept, therapeutic strategies for schizophrenia could be the modification of the gut microbiota. Probiotics and/or fecal microbiota transplantation are now emerging as the most promising treatments for the modification. More consideration of the roles of gut microbiota will conduct the further development of immune-based therapeutics for the prevention and/or treatments of psychiatric disorders.

The cholesterol is a vital component of cell membranes and myelin sheaths, and a precursor for essential molecules such as steroid hormones. In humans, cholesterol is partially obtained through the diet, while the majority is synthesized in the body, primarily in the liver. However, the limited exchange between the central nervous system and peripheral circulation, due to the presence of the blood-brain barrier, necessitates cholesterol in the brain to be exclusively acquired from local de novo synthesis. This cholesterol is reutilized efficiently, rendering a much slower overall turnover of the compound in the brain as compared with the periphery. Furthermore, brain cholesterol is regulated independently from peripheral cholesterol. Numerous enzymes, proteins, and other factors are involved in cholesterol synthesis and metabolism in the brain. Understanding the unique mechanisms and pathways involved in the maintenance of cholesterol homeostasis in the brain is critical, considering perturbations to these processes are implicated in numerous neurodegenerative diseases. This review focuses on the developing understanding of cholesterol metabolism in the brain, discussing the sites and processes involved in its synthesis and regulation, as well as the mechanisms involved in its distribution throughout, and elimination from, the brain.

Phosphoinositides are membrane phospholipids involved in a variety of cellular processes like growth, development, metabolism, and transport. This review focuses on the maintenance of cellular homeostasis of phosphatidylinositol 4,5-bisphosphate (PIP₂), and phosphatidylinositol 3,4,5-trisphosphate (PIP₃). The critical balance of these PIPs is crucial for regulation of neuronal form and function. The activity of PIP₂ and PIP₃ can be regulated through kinases, phosphatases, phospholipases and cholesterol microdomains. PIP₂ and PIP₃ carry out their functions either indirectly through their effectors activating integral signaling pathways, or through direct regulation of membrane channels, transporters, and cytoskeletal proteins. Any perturbations to the balance between PIP₂ and PIP₃ signaling result in neurodevelopmental and neurodegenerative disorders. This review will discuss the upstream modulators and downstream effectors of the PIP₂ and PIP₃ signaling, in the context of neuronal health and disease.

Early in the course of infection, human immunodeficiency virus (HIV) is able to enter the central nervous system where it stablishes a permanent reservoir. Current antiretroviral therapies do not efficiently cross the blood-brain barrier and therefore do not reach the HIV located in the central nervous system. Consequently, HIV infection can often be associated with neurocognitive impairment and HIV-associated dementia. The purpose of this review is to brief the reader into the world of neurological complications arising from HIV infection. Mechanisms by which HIV directly or indirectly impairs the central nervous system are discussed, as well as other factors influencing or contributing to the impairment, and the animal models currently used to perform research on the topic.

Since the identification and cloning of the cannabinoid receptor 2 (CB₂R), several studies focused on the characterization of its physiological and pathological role. Initially, CB₂R was considered as the peripheral cannabinoid receptor due to its detection in the rat spleen and leukocyte subpopulation in humans. Later, CB₂R was identified in different brain regions significantly modifying the landscape and pointing out its role in a wide variety of central physiological functions and pathological conditions. Additional research also detected the expression of CB₂R in neurons, microglia, and astroglia in different brain regions. Indeed, the findings collected to date support a significant function of CB₂R in anxiety, depression, schizophrenia, and additional neuropsychiatric disorders. This review gathers the most relevant literature regarding new advances about the role of CB₂R in a variety of neuropsychiatric conditions, with special emphasis on its potential as a new therapeutic target for the treatment of different psychiatric disorders.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting 1% of the population above sixty years. It is caused by an interaction between genetic and environmental risk factors. Loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) is pathologically characterizing the disease and responsible for the cardinal motor symptoms, most notably, bradykinesia, rest tremors, rigidity, and loss of postural reflexes. Non-motor signs such as olfactory deficits, cognitive impairment, sleep behavior disorders, and gastrointestinal disturbances are reflecting disturbances in the non-dopaminergic system. They precede dopaminergic neuronal degenerations by 5–10 years and are considered the main contributors to patients’ disability, particularly after the successful implementation of levodopa (L-dopa) treatment of motor symptoms. The present general review aimed to briefly update non-motor signs and their underlying pathophysiology in PD.

Peroxisomes are actively involved in the metabolism of various lipids including fatty acids, ether phospholipids, bile acids as well as the processing of reactive oxygen and nitrogen species. Recent studies show that peroxisomes can regulate cholesterol homeostasis by mediating cholesterol transport from the lysosomes to the endoplasmic reticulum and towards primary cilium as well. Disruptions of peroxisome biogenesis or functions lead to peroxisomal disorders that usually involve neurological deficits. Peroxisomal dysfunction is also linked to several neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In many peroxisomal disorders and neurodegenerative diseases, aberrant cholesterol accumulation is frequently encountered yet largely neglected. This review discusses the current understanding of the mechanisms by which peroxisomes facilitate cholesterol trafficking within the cell and the pathological conditions related to impaired cholesterol transport by peroxisomes, with the hope to inspire future development of the treatments for peroxisomal disorders and neurodegenerative diseases.

Acute ischemic stroke (AIS) is the leading cause of disability and one of the top causes of mortality worldwide. The current standard of care is reperfusion therapy including intravenous thrombolysis (IVT) and thrombectomy. However, these treatments have limitations as they have a limited therapeutic window. Hence, there is a vital need to develop neuroprotective agents to prevent brain injury, extend the reperfusion window, improve mortality, and reduce disability in AIS patients. Neuroprotective agents work by counteracting the detrimental biochemical and molecular events that result in irreversible ischemic damage. Numerous preclinical studies and clinical trials have been done on different agents. Thus far, all have been definitively unsuccessful in large trials. Currently, there are several challenges in translation from animal studies to human trials. It is important to understand the current evidence as well as past challenges in the development of neuroprotective strategies in AIS in order for a more strategic selection of agents to be studied, improve study designs and thus contribute to the development of effective neuroprotective agents. Newer agents have shown promise in neuroprotection, and human trials are ongoing. In this review, the mechanisms of action of different families of neuroprotective agents were discussed. The evidence for the efficacy of different drugs in each family of neuroprotective agents was also evaluated and the current research landscape in neuroprotection for AIS was summarized. The past challenges and limitations in clinical trials and proposed possible ways to address these issues were highlighted.

Current evidence indicates that neurodegeneration of dopaminergic neurons of the substantia nigra associated to Parkinson’s disease is a consequence of a neuroinflammatory process in which microglial cells play a central role. The initial activation of microglial cells is triggered by pathogenic protein inclusions, which are mainly composed by α-synuclein. Importantly, these pathogenic forms of α-synuclein subsequently induce a T-cell-mediated autoimmune response to dopaminergic neurons. Depending on their functional phenotype, these autoreactive T-cells might shape the functional features of activated microglia. T-cells bearing pro-inflammatory phenotypes such as T-helper (Th)1 or Th17 promote a chronic inflammatory behaviour on microglia, whilst anti-inflammatory T-cells, such as regulatory T-cells (Treg) favour the acquisition of neuroprotective features by microglia. Thus, T-cells play a fundamental role in the development of neuroinflammation and neurodegeneration involved in Parkinson’s disease. This review summarizes the evidence indicating that not only CD4⁺ T-cells, but also CD8⁺ T-cells play an important role in the physiopathology of Parkinson’s disease. Next, this review analyses the different T-cell epitopes derived from the pathogenic forms of α-synuclein involved in the autoimmune response associated to Parkinson’s disease in animal models and humans. It also summarizes the requirement of specific alleles of major histocompatibility complexes (MHC) class I and class II necessaries for the presentation of CD8⁺ and CD4⁺ T-cell epitopes from the pathogenic forms of α-synuclein in both humans and animal models. Finally, this work summarizes and discusses a number of experimental immunotherapies that aim to strengthen the Treg response or to dampen the inflammatory T-cell response as a therapeutic approach in animal models of Parkinson’s disease.