Ari Rappoport

I present a theory of Alzheimer's disease (AD) that explains its symptoms, pathology, and risk factors. To do this, I introduce a new theory of brain plasticity that elucidates the physiological roles of AD-related agents. New events generate synaptic and branching candidates competing for long-term enhancement. Competition resolution crucially depends on the formation of membrane lipid rafts, which requires astrocyte-produced cholesterol. Sporadic AD is caused by impaired formation of plasma-membrane lipid rafts, preventing the conversion of short- to long-term memory and yielding excessive tau phosphorylation, intracellular cholesterol accumulation, synaptic dysfunction, and neurodegeneration. Amyloid β (Aβ) production is promoted by cholesterol during the switch to competition resolution, and cholesterol accumulation stimulates chronic Aβ production, secretion, and aggregation. The theory addresses all of the major established facts known about the disease and is supported by strong evidence.

I present a complete theory of Parkinson’s disease (PD). PD involves an abundance of gut microbiota that degrade mucin, resulting in elevated brain uptake of galactose (a mucin component) and reduced uptake of glucose. Since galactose is not efficiently used for glycolysis, this decreases the production of glutathione, which is essential for countering oxidative iron toxicity. The brain cells that are most sensitive to this effect, as attested by their expression of the iron chelator neuromelanin, are those that continuously secrete dopamine and norepinephrine, and they eventually degenerate. This account explains the etiology, symptoms (including prodromal autonomic symptoms), pathology and risk factors of the disease. The theory is supported by strong evidence, and gives rise to several relatively simply directions for early identification and treatment of the disease.

I present a biological theory of anorexia nervosa (AN) and bulimia nervosa (BN). AN and BN are caused by stress-induced corticotropin-releasing hormone (CRH) that chronically activates the CRH2 and CRH1 receptors, respec- tively. The physiological role of CRH2 is to trigger responses to excess states, recruiting serotonin to reduce food intake and gut activity and promote white adi- pose tissue growth. The role of CRH1 is to respond to deficiency states, promoting food intake. I show that chronic activation of the two receptors can explain the symptoms and properties of the two disorders. In particular, refusing to eat, binge eating, purging behavior (e.g., vomiting, usage of laxatives), and claiming to be too fat are rational responses to concrete biological signals. The theory is supported by strong evidence and points to several novel treatment directions.

Amyotrophic lateral sclerosis (ALS) is a devastating disease whose etiology is currently unknown. This paper presents a novel theory in which ALS is caused by an impairment of the alpha2de;ta subunit of voltage-gated calcium channels (VGCCs), most likely due to autoimmune targeting. I show how the impairment mechanistically induces chronic calcium, which in turn explains the major clinical, epidemiological, and pathological evidence known about the disease. The same theory explains the major variant of frontotemporal dementia (FTD) that greatly overlaps with ALS.

This paper presents a new theory explaining the pathological mechanisms of multiple sclerosis (MS). MS is triggered by persistently activated immune cells, mainly B cells, as in reactivated Epstein-Barr virus infection. Activated immune cells release cytokines, the main one here being TNFa. A major role of TNFa is to support immune cell motility and tissue penetration, by promoting the breakdown of ceramide products that stabilize membranes (sphingomyelin (SPM) and galactosylceramide (GalCer)), by stimulating membrane breakdown via ceramide 1-phosphate-induced liberation of arachidonic acid, and by promoting the production of sphingosine 1-phosphate, a ceramide product that promotes immune motility. These ceramide products are expressed in endothelial cells, including the blood-brain barrier, and have a large presence in myelin. Thus, excessive cytokine release both allows immune penetration into the brain, and impairs existing myelin sheaths. SPM and GalCer are essential for myelin maintenance but not for its synthesis, explaining the dominant relapsing-remitting nature of the disease. The theory is supported by diverse evidence, and supports modern B cell-based treatment directions.

I present the first complete theory of ADHD. ADHD occurs when the organism adapts to try to maintain higher glucose levels than normal. The main mechanism via which this is done is by faster opening of KATP channels, mainly Kir6.2/SUR1, which increases the cell's intrinsic \xtblty. I show that this induces all of the symptoms of ADHD. The optimal treatment for ADHD already exists, since drugs of the sulfonylurea family close KATP channels and have been used for safely treating people for dozens of years.

I present a theory of schizophrenia (SZ) that mechanistically explains its etiology, symptoms, pathophysiology, and treatment. SZ involves the chronic release of membrane polyunsaturated fatty acids (PUFAs) and their utilization for the synthesis of stress-induced plasticity agents such as endocannabinoids (ECBs). The causal event in SZ is prolonged stress during a sensitive period, which can induce prolonged and heritable changes. The physiological effect of the released PUFAs and their products is to disconnect neurons from their inputs and promote intrinsic excitability. I show that these effects can explain the positive, negative, cognitive, and mood symptoms of SZ, as well as the mechanisms of many known triggers of psychosis. The theory is supported by overwhelming evidence addressing lipids, immunity, ECBs, neuromodulators, hormones, neurotransmitters, and cortical parameters in SZ. It explains why antipsychotic drugs are effective against positive symptoms, and why they do not affect the other symptoms. Finally, I present promising treatment directions implied by the theory, including some that are immediately available.

Migraine (MGR) ranks first among diseases in terms of years of lost healthy life in young adult and adult women. Currently, there is no theory of MGR. This paper presents a complete theory of migraine that explains its etiology, symptoms, pathology, and treatment. Migraine involves partially saturated (usually chronically high) sympathetic nervous system (SNS) activity, mainly due to higher sensitivity of the metabolic sensors that recruit it. MGR headache occurs when SNS activity is desensitized or excessive, resulting in hyperexcitability of baroreceptors, oxidative stress, and activation of pain pathways via TRPV1 channels and CGRP. The theory is supported by overwhelming evidence, and explains the properties of current MGR treatments.

Major depressive disorder (MDD) is a debilitating health condition affecting a substantial part of the world's population. At present, there is no biological theory of MDD, and treatment is partial at best. Here I present a theory of MDD that explains its etiology, symptoms, pathophysiology, and treatment. MDD involves stressful life events that the person does not manage to resolve. In this situation animals normally execute a 'disengage' survival response. In MDD, this response is chronically executed, leading to depressed mood and the somatic MDD symptoms. To explain the biological mechanisms involved, I present a novel theory of opioids, where each opioid mediates one of the basic survival responses. The opioid mediating 'disengage' is dynorphin. The paper presents strong evidence for chronic dynorphin signaling in MDD and for its causal role in the disorder. The theory also explains bipolar disorder, and the mechanisms behind the treatment of both disorders.

This paper presents a complete theory of autism spectrum disorder (ASD), explaining its etiology, symptoms, and pathology. The core cause of ASD is excessive stress-induced postnatal release of corticotropin-releasing hormone (CRH). CRH competes with urocortins for binding to the CRH2 receptor, impairing their essential function in the utilization of glucose for growth. This results in impaired development of all brain areas depending on CRH2, including areas that are central in social development and eye gaze learning, and low-level sensory areas. Excessive CRH also induces excessive release of adrenal androgens (mainly DHEA), which impairs the long-term plasticity function of gonadal steroids. I show that these two effects can explain all of the known symptoms and properties of ASD. The theory is supported by strong diverse evidence, and points to very early detection biomarkers and preventive pharmaceutical treatments, one of which seems to be very promising.