Stress induced neural reorganization: A conceptual framework linking depression and Alzheimer's disease

Abstract

Chronic stress is a risk factor for a number of physiological disorders including cardiovascular disease, obesity and gastrointestinal disorders, as well as psychiatric and neurodegenerative disorders. There are a number of underlying molecular and cellular mechanisms altered in the course of chronic stress, which may increase the vulnerability of individuals to develop psychiatric disorders such as depression, and neurodegenerative disorders such as Alzheimer's Disease (AD). This is evident in the influence of stress on large-scale brain networks, including the resting state Default Mode Network (DMN), the effects of stress on neuronal circuitry and architecture, and the cellular and molecular adaptations to stress, which may render individuals with stress related psychiatric disorders more vulnerable to neurodegenerative disease later in life. These alterations include decreased negative feedback inhibition of the hypothalamic pituitary axis (HPA) axis, decreased dendritic arborization and spine density in the prefrontal cortex (PFC) and hippocampus, and the release of proinflammatory cytokines, which may suppress neurogenesis and promote neuronal cell death. Each of these factors are thought to play a role in stress-related psychiatric disease as well as AD, and have been observed in clinical and post-mortem studies of individuals with depression and AD. The goal of the current review is to summarize clinical and preclinical evidence supporting a role for chronic stress as a putative link between neuropsychiatric and neurodegenerative disease. Moreover, we provide a rationale for the importance of taking a medical history of stress-related psychiatric diseases into consideration during clinical trial design, as they may play an important role in the etiology of AD in stratified patient populations.

Keywords: Adrenergic receptors; Amyloid; Depression; Dopamine-β-hydroxylase; Norepinephrine; Stress.

Figure 1

Cellular mechanisms of amyloid β (Aβ) production and secretion from somatodendritic and synaptic sites. This schematic reflects hypothetical and known mechanisms of Aβ production and secretion described in the literature with respect to locus coeruleus (LC)- norepinephrine (NE) circuitry. Figure 1a. points to the synaptic cleft of a corticotropin releasing factor (CRF) terminal releasing CRF onto and LC dendrite. Box 1A shows a higher magnification image of CRF release onto LC neurons under conditions of stress, engaging CRF Receptor 1, which has been implicated in Aβ production and abnormal phosphorylated tau (taup). Figure 1b. illustrates amyloid precursor protein (APP) processing within the soma of LC neurons. Box 1B. expands on the mechanistic details of APP processing within the cell body, illustrating that the subcellular localization of APP determines its participation in two divergent processing pathways: the α-secretase mediated non-amyloidogenic pathway, or the beta amyloid cleaving enzyme 1 (BACE-1) and γ-secretase mediated amyloidogenic pathway. Once Aβ is formed, it may continue along the secretory pathway, resulting in release into the extracellular space, or degradation in the lysosome (Haass, Kaether et al. 2012). Studies utilizing microdialysis have estimated that approximately 30% of endogenous interstitial fluid (ISF) Aβ is produced in the secretory pathway and released from somatodendritic processes (Box 1B), while approximately 60% is produced at the synapse (Cirrito, May et al. 2003) (Figure 1c). Box 1C illustrates that the production and secretion of Aβ at the synapse is a tightly regulated process that occurs following changes in synaptic activity, in an endocytosis dependent manner (Cirrito, Yamada et al. 2005, Cirrito, Kang et al. 2008). It has been hypothesized that increases in synaptic activity correlate with increased vesicle recycling, which leads to greater internalization of APP, and subsequent increased amyloidogenic processing (Cirrito, Kang et al. 2008). Microdialysis studies utilizing acute behavior paradigms of stress or exogenous CRF have demonstrated increased levels of ISF levels of Aβ (Kang, Cirrito et al. 2007), however, the anatomical substrates of this interaction with respect to LC neurons has not yet been investigated.

Figure 2

Putative consequences of Aβ accumulation in stress-related psychiatric disorders. We propose that chronic stress results in the production and accumulation of Aβ in the PFC, initiating mechanisms of post synaptic depression. With decreased activity of PFC neurons, other limbic regions such as the amygdala may become hyperactive, exhibiting increased dendritic spine density. As a result, a potential feed-forward system may be engaged, creating a vicious cycle in which imbalances in neurotransmitters and neuronal activity are perpetuated, and may manifest behaviorally as a stress-related psychiatric disorder such as anxiety or depression. LTD, long term depression.

Figure 3

Hypothesized influence of coeruleo-cortical network dysregulation on AD progression. Based on the cumulative evidence in the literature, we hypothesize that In the fifteen to twenty years prior to the onset of cognitive symptoms of AD, stress induced chronic activation of the LC and corresponding increases in noradrenergic transmission increases Aβ production, secretion and accumulation in cortical regions such as the infralimbic medial PFC. Further, we hypothesize that the aberrant accumulation of Aβ peptides results in a disconnection in communication, or desynchronization, between the LC and its cortical efferent projections.