Neurodevelopmental and Neurodegenerative Disorders: Molecular Mechanisms and Therapeutic Strategies

Background/Objectives. Obesity, type 2 diabetes (T2D), and Alzheimer’s disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy and are difficult to prevent and control when they develop. It has been known for many years that these diseases have many pathogenic aspects in common. We highlight in this review that neuroglial cells (astroglia, oligodendroglia, and microglia) play a vital role in the origin, clinical–pathological development, and course of brain neurodegeneration. Moreover, we include the new results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we are investigating. Methods. Critical bibliographic revision and biochemical neuropathological study of neuroglia in a T2D-AD model. Results. T2D and AD are not only “connected” by producing complex pathologies in the same individual (obesity, T2D, and AD), but they also have many common pathogenic mechanisms. These include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, mitochondrial dysfunction, and inflammation (both peripheral and central—or neuroinflammation). Cognitive impairment and AD are the maximum exponents of brain neurodegeneration in these pathological processes. both due to the dysfunctions induced by metabolic changes in peripheral tissues and inadequate neurotoxic responses to changes in the brain. In this review, we first analyze the common pathogenic mechanisms of obesity, T2D, and AD (and/or cerebral vascular dementia) that induce transcendental changes and responses in neuroglia. The relationships between T2D and AD discussed mainly focus on neuroglial responses. Next, we present neuroglial changes within their neuropathological context in diverse scenarios: (a) aging involution and neurodegenerative disorders, (b) human obesity and diabetes and obesity/diabetes models, (c) human AD and in AD models, and (d) human AD-T2D and AD-T2D models. An important part of the data presented comes from our own studies on humans and experimental models over the past few years. In the T2D-AD section, we included the results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we investigated, which showed that neuroglial dysfunctions (astrocytosis and microgliosis) manifest before the appearance of amyloid neuropathology, and that the amyloid pathology is greater than that presented by mice fed a normal, non-high-caloric diet A broad review is finally included on pharmacological, cellular, genic, and non-pharmacological (especially diet and lifestyle) neuroglial-related treatments, as well as clinical trials in a comparative way between T2D and AD. These neuroglial treatments need to be included in the multimodal/integral treatments of T2D and AD to achieve greater therapeutic efficacy in many millions of patients. Conclusions. Neuroglial alterations (especially in astroglia and microglia, cornerstones of neuroinflammation) are markedly defining brain neurodegeneration in T2D and A, although there are some not significant differences between each of the studied pathologies. Neuroglial therapies are a very important and p. promising tool that are being developed to prevent and/or treat brain dysfunction in T2D-AD. The need for further research in two very different directions is evident: (a) characterization of the phenotypic changes of astrocytes and microglial cells in each region of the brain and in each phase of development of each isolated and associated pathology (single-cell studies are mandatory) to better understand the pathologies and define new therapeutic targets; (b) studying new therapeutic avenues to normalize the function of neuroglial cells (preventing neurotoxic responses and/or reversing them) in these pathologies, as well as the phenotypic characteristics in each moment of the course and place of the neurodegenerative process. Full article

Background. The majority of deaths in patients with schizophrenia and other severe mental illnesses (SMIs) are caused by natural causes, such as cardiovascular diseases (CVDs). The increased risk of CVD and other somatic diseases in SMIs cannot be fully explained by the contribution of traditional risk factors, behavioral risk factors, patients’ lifestyle peculiarities, and the influence of antipsychotics. The present review has the following main objectives: (1) to aggregate evidence that neurodevelopmental disorders are the basis of SMIs; (2) to provide a review of studies that have addressed the shared genetic architecture of SMI and cardiovascular disease; and (3) to propose and substantiate the consideration of somatic diseases as independent endophenotypes of SMIs, which will make it possible to place the research of somatic diseases in SMIs within the framework of the concepts of the “neurodevelopmental continuum and gradient” and “endophenotype”. Methods. A comprehensive literature search was performed on 1 July 2024. The search was performed using PubMed and Google Scholar databases up to June 2024. Results. The current literature reveals considerable overlap between the genetic susceptibility loci for SMIs and CVDs. We propose that somatic diseases observed in SMIs that have a shared genetic architecture with SMIs can be considered distinct physical health-related endophenotypes. Conclusions. In this narrative review, the results of recent studies of CVDs in SMIs are summarized. Reframing schizophrenia as a multisystem disease should contribute to the activation of new research on somatic diseases in SMIs. Full article