Dual Role of Autophagy in Diseases of the Central Nervous System

Autophagy is a vital lysosomal degradation and recycling pathway in the eukaryotic cell, responsible for maintaining an intricate balance between cell survival and cell death, necessary for neuronal survival and function. This dual role played by autophagy raises the question whether this process is a protective or a destructive pathway, the contributor of neuronal cell death or a failed attempt to repair aberrant processes? Deregulated autophagy at different steps of the pathway, whether excessive or downregulated, has been proposed to be associated with neurodegenerative disorders such as Alzheimer’s-, Huntington’s-, and Parkinson’s-disease, known for their intracellular accumulation of protein aggregates. Recent observations of impaired autophagy also appeared in psychiatric disorders such as schizophrenia and bipolar disorder suggesting an additional contribution to the pathophysiology of mental illness. Here we review the current understanding of autophagy’s role in various neuropsychiatric disorders and, hitherto, the prevailing new potential autophagy-related therapeutic strategies for their treatment

Is There Justification to Treat Neurodegenerative Disorders by Repurposing Drugs? The Case of Alzheimer’s Disease, Lithium, and Autophagy

Lithium is the prototype mood-stabilizer used for acute and long-term treatment of bipolar disorder. Cumulated translational research of lithium indicated the drug’s neuroprotective characteristics and, thereby, has raised the option of repurposing it as a drug for neurodegenerative diseases. Lithium’s neuroprotective properties rely on its modulation of homeostatic mechanisms such as inflammation, mitochondrial function, oxidative stress, autophagy, and apoptosis. This myriad of intracellular responses are, possibly, consequences of the drug’s inhibition of the enzymes inositol-monophosphatase (IMPase) and glycogen-synthase-kinase (GSK)-3. Here we review lithium’s neurobiological properties as evidenced by its neurotrophic and neuroprotective properties, as well as translational studies in cells in culture, in animal models of Alzheimer’s disease (AD) and in patients, discussing the rationale for the drug’s use in the treatment of AD

The Effect of Global Warming on Complex Disorders (Mental Disorders, Primary Hypertension, and Type 2 Diabetes)

Multiple studies imply a strong relationship between global warming (GW) and complex disorders. This review summarizes such reports concentrating on three disorders—mental disorders (MD), primary hypertension, and type 2 diabetes (T2D). We also attempt to point at potential mechanisms mediating the effect of GW on these disorders. Concerning mental disorders, immediate candidates are brain levels of heat-shock proteins (HSPs). In addition, given that heat stress increases reactive oxygen species (ROS) levels which may lead to blood–brain barrier (BBB) breakdown and, hence, enhanced protein extravasation in the brain, this might finally cause, or exacerbate mental health. As for hypertension, since its causes are incompletely understood, the mechanism(s) by which heat exposure affects blood pressure (BP) is an open question. Since the kidneys participate in regulating blood volume and BP they are considered as a site of heat-associated disease, hence, we discuss hyperosmolarity as a potential mediator. In addition, we relate to autoimmunity, inflammation, sodium excretion, and HSP70 as risk factors that might play a role in the effect of heat on hypertension. In the case of T2D, we raise two potential mediators of the effect of exposure to ambient hot environment on the disease’s incidence—brown adipose tissue metabolism and HSPs

Neuroinflammation as a Common Denominator of Complex Diseases (Cancer, Diabetes Type 2, and Neuropsychiatric Disorders)

The term neuroinflammation refers to inflammation of the nervous tissue, in general, and in the central nervous system (CNS), in particular. It is a driver of neurotoxicity, it is detrimental, and implies that glial cell activation happens prior to neuronal degeneration and, possibly, even causes it. The inflammation-like glial responses may be initiated in response to a variety of cues such as infection, traumatic brain injury, toxic metabolites, or autoimmunity. The inflammatory response of activated microglia engages the immune system and initiates tissue repair. Through translational research the role played by neuroinflammation has been acknowledged in different disease entities. Intriguingly, these entities include both those directly related to the CNS (commonly designated neuropsychiatric disorders) and those not directly related to the CNS (e.g., cancer and diabetes type 2). Interestingly, all the above-mentioned entities belong to the same group of “complex disorders”. This review aims to summarize cumulated data supporting the hypothesis that neuroinflammation is a common denominator of a wide variety of complex diseases. We will concentrate on cancer, type 2 diabetes (T2DM), and neuropsychiatric disorders (focusing on mood disorders)