Neuroprotection in Autism, Schizophrenia and Alzheimer's disease

Illana Gozes, Joseph Levine

• Publisher: Academic Press
• Year: 2019
• Print ISBN: 9780128140376
• eBook ISBN: 9780128140383
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

Neuroprotection in Autism, Schizophrenia and Alzheimer's Disease provides an up-to-date overview on recent clinical studies and the similarities discovered in the most prevalent brain disorders. The book's content will help shed light on basic mechanisms and provide new avenues for early diagnosis toward disease prevention and disease modification. It is written for researchers, clinicians and medical physicians in neuroscience, neurology and psychiatry. Sections discuss the shared pathophysiological mechanisms that underlie autism, schizophrenia/mood disorders and Alzheimer's disease, i.e. neurodevelopmental disorders, neuropsychiatric diseases and neurodegenerative disorders.- Offers an up-to-date overview of basic and clinical studies concerning similarities in the most prevalent brain disorders- Helps the reader become familiar with novel neuroprotective mechanisms and experimental treatment modalities in these difficult to treat disorders- Written for researchers, clinicians and medical physicians in neuroscience, neurology and psychiatry

Section III

Neuropsychiatric disorders

Chapter 6

Neuroprotective roles of neurotrophic factors in depression

Christina Gross^a,b; Kim B. Seroogy^{c a} Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^b Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^c Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH, United States

Abstract

Depression is a mood disorder associated with consistent feelings of sadness, worthlessness, and guilt, as well as the loss of interest and pleasure. Genetic and environmental factors, such as adverse early-life events, are believed to contribute to depression, but the underlying mechanisms are not fully understood. Increasing evidence suggests that impaired neurotrophic factor expression or signaling may be a shared pathological mechanism of depression and a potential treatment target. Altered neurotrophic signaling may also contribute to comorbid depression in neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. This chapter will provide a concise overview of impaired neurotrophic factor signaling in depression and comment on how impaired neuroprotection may contribute to depressive disorders in neurodegenerative diseases. We will discuss some of the ongoing efforts to target these defects in neurotrophic factor signaling for therapeutic treatment and explain what is needed to fully exploit altered neurotrophic factor signaling as a treatment target in depression and neurodegenerative disorders associated with depression.

Keywords

Depression; Major depressive disorder; Chronic stress; Neurotrophic factors; BDNF; TrkB; Neurogenesis; Neuroinflammation; Neurotoxicity; Parkinson’s disease

Acknowledgments

The authors apologize to all neuroscientists whose important work could not be cited due to space limitations. CG is supported by NIH grants R01NS092705 and R21HD090333, a 2017 Independent Investigator Award from the Brain and Behavior Research Foundation and the Cincinnati Children’s Research Foundation. KBS is supported by a grant from the University of Cincinnati Gardner Neuroscience Institute-Neurobiology Research Center, the Selma Schottenstein Harris Lab for Research in Parkinson’s, the Gardner Family Center for Parkinson’s Disease and Movement Disorders, the Parkinson’s Disease Support Network of Ohio, Kentucky and Indiana, and the Kerman Family Fund.

Introduction

Mood disorders comprise a subset of neuropsychiatric diseases characterized by pathological disturbances in an individual’s mood, which are often long-lasting and may change abruptly. The most common mood disorders are depression, bipolar disorder, and schizoaffective disorder. Mounting evidence suggests that impairments in neurotrophic factor expression or signaling contribute to these disorders and may be potential treatment targets. Defects at the cellular level associated with depression, such as reduced neurogenesis, elevated risk for neuroinflammation, and increased vulnerability to neurotoxicity, can all be explained by deficiencies in signaling through neurotrophic factors. Insufficient neurotrophic stimuli in mood disorders are not directly linked to neurodegeneration; however, the underlying mechanisms and resulting potential therapeutic targets are shared with neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. Notably, many neurodegenerative diseases are associated with depression suggesting overlapping disease etiologies and neuropathological substrates. In this chapter, we will provide a concise overview of impaired neurotrophic factor signaling in depression and comment on how impaired neuroprotection may contribute to symptoms of depression in neurodegenerative diseases associated with depressive disorders. We will discuss some of the ongoing efforts to target these defects in neurotrophic factor signaling for therapeutic treatment and explain what is needed to fully exploit altered neurotrophic factor signaling as a treatment target in depression and in neurodegenerative disorders with comorbid depression.

The need for novel treatment strategies in depression

Depression is a mood disorder associated with consistent feelings of sadness, worthlessness, and guilt, as well as the loss of interest and pleasure. Other symptoms include insomnia or hypersomnia, changes in appetite and weight, fatigue, inability to focus, and indecisiveness. Together, these symptoms have a huge negative impact on the quality of life of affected individuals and impair their relationships with family and friends as well as their productivity in the work force.¹ The most severe form of depression, major depressive disorder (MDD), is defined as experiencing at least five of these symptoms during a 2-week period (The Diagnostic and Statistical Manual of Mental Disorders, 5th edition [DSM-5]).² Individuals with MDD are at risk for suicide and often need lifelong treatment. Current therapeutic treatments for depression include antidepressant medications (e.g., selective serotonin reuptake inhibitors, SSRIs, and most recently a form of the fast-acting NMDA receptor antagonist, ketamine), deep brain stimulation, and psychotherapy.³ Up to 50% of all individuals with depression, especially those falling under the category of MDD, are treatment resistant.⁴ Treatment resistance can even evolve over time, which poses a constant challenge to affected individuals and their clinical providers to identify alternative treatments.⁵

The etiology of depression is multifaceted. Genetic and environmental factors, such as chronic stress and early-life adverse events, have been identified as disease contributors.^6–8 Depressive disorders are also frequently associated with neurodegenerative disorders, for example Alzheimer’s disease,⁹ frontotemporal dementia,¹⁰ Parkinson’s disease,¹¹ amyotrophic lateral sclerosis,¹² and multiple sclerosis,¹³ worsening the associated conditions and often complicating the treatment of affected individuals. The high incidence of depression in neurodegenerative disorders suggests shared underlying pathomechanisms of the two diseases, which may offer novel treatment targets. In this chapter, we will discuss current evidence that one of these shared etiologies may be impaired neuroprotection mediated by insufficient neurotrophic factor signaling.

Evidence suggestive of impaired neuroprotection and neurotrophic factors signaling in depression

A role for the loss of neuroprotection and altered neurotrophic factor signaling in depression has been supported by various findings in both humans and animal models. Those findings range from brain imaging, postmortem brain analyses, and quantification of blood serum levels of neurotrophic factors in humans with depr...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• About the editors
• Introduction
• Section I: Overview
• Section II: Autism
• Section III: Neuropsychiatric disorders
• Section IV: Alzheimer and neurodegenerative diseases
• Index