Targeting the cannabinoid system to counteract the deleterious effects of stress in Alzheimer's disease.

Alzheimer's disease is a progressive neurodegenerative disorder characterized histologically in postmortem human brains by the presence of dense protein accumulations known as amyloid plaques and tau tangles. Plaques and tangles develop over decades of aberrant protein processing, post-translational modification, and misfolding throughout an individual's lifetime. We present a foundation of evidence from the literature that suggests chronic stress is associated with increased disease severity in Alzheimer's patient populations. Taken together with preclinical evidence that chronic stress signaling can precipitate cellular distress, we argue that chronic psychological stress renders select circuits more vulnerable to amyloid- and tau- related abnormalities. We discuss the ongoing investigation of systemic and cellular processes that maintain the integrity of protein homeostasis in health and in degenerative conditions such as Alzheimer's disease that have revealed multiple potential therapeutic avenues. For example, the endogenous cannabinoid system traverses the central and peripheral neural systems while simultaneously exerting anti-inflammatory influence over the immune response in the brain and throughout the body. Moreover, the cannabinoid system converges on several stress-integrative neuronal circuits and critical regions of the hypothalamic-pituitary-adrenal axis, with the capacity to dampen responses to psychological and cellular stress. Targeting the cannabinoid system by influencing endogenous processes or exogenously stimulating cannabinoid receptors with natural or synthetic cannabis compounds has been identified as a promising route for Alzheimer's Disease intervention. We build on our foundational framework focusing on the significance of chronic psychological and cellular stress on the development of Alzheimer's neuropathology by integrating literature on cannabinoid function and dysfunction within Alzheimer's Disease and conclude with remarks on optimal strategies for treatment potential.

Dietary sugar intake and risk of Alzheimer's disease in older women.

BACKGROUND: Despite some reports of cardiometabolic disorders associated with the risk of Alzheimer's disease (AD), limited studies have been conducted to examine the association between excessive sugar intake (a risk factor for cardiometabolic disorders) and AD risk. AIM: The purpose of our study was to evaluate if excessive sugar intake has a significant long-term effect on the risk of AD. METHODS: A population sample of 37,689 participants, who enrolled in the United States (US) Women's Health Initiative - Dietary Modification Trial (WHI-DM) in 1993-2005 and its extended observational follow-up study through 1 March 2019, were analyzed. Dietary sugar intake was measured using food frequency questionnaires. AD was classified by reports using a standard questionnaire. A dietary pattern that explained the maxima variations in sugar intake was constructed using reduced rank regression (RRR) technique. Associations of RRR dietary pattern scores and sugar intake (g/day) by quartiles (Q1 through Q4) with AD risk were examined using Cox proportional hazards regression analysis with adjusting for key covariates. RESULTS: During a mean follow-up of 18.7 years, 4586 participants reported having incident AD. The total incidence rate (95% confidence interval [CI]) of AD was 6.5 (6.3-6.7) per 1000 person-years (PYs). The incidence rates (95% CI) of AD by total sugar intake were 6.2 (5.8-6.6), 6.4 (6.0-6.8), 6.6 (6.3-7.0), and 6.9 (6.5-7.3) per 1000 PYs among those in quartiles (Q) 1 to Q4 (toward higher sugar consumption) of total sugar intake, respectively (test for trend of AD incident rates, p < 0.001). Individuals in Q4 of total sugar intake had a 1.19 higher risk of incident AD than those in Q1 (hazard ratio [HR] = 1.19, 95% CI: 1.05-1.34, p = 0.01). An estimated increase of 10 g/day in total sugar intake (about 2.4 teaspoons) was associated with an increased AD risk by 1.3-1.4%. Of six subtypes of sugar intake, lactose was significantly associated with AD risk. CONCLUSIONS: Our study indicates that excessive total sugar intake was significantly associated with AD risk in women. Of six subtypes of sugar intake, lactose had a stronger impact on AD risk.

Combining Laser Capture Microdissection and Microfluidic qPCR to Analyze Transcriptional Profiles of Single Cells: A Systems Biology Approach to Opioid Dependence.

Profound transcriptional heterogeneity in anatomically adjacent single cells suggests that robust tissue functionality may be achieved by cellular phenotype diversity. Single-cell experiments investigating the network dynamics of biological systems demonstrate cellular and tissue responses to various conditions at biologically meaningful resolution. Herein, we explain our methods for gathering single cells from anatomically specific locations and accurately measuring a subset of their gene expression profiles. We combine laser capture microdissection (LCM) with microfluidic reverse transcription quantitative polymerase chain reactions (RT-qPCR). We also use this microfluidic RT-qPCR platform to measure the microbial abundance of gut contents.

The role of catecholamines in modulating responses to stress: Sex-specific patterns, implications, and therapeutic potential for post-traumatic stress disorder and opiate withdrawal.

Emotional arousal is one of several factors that determine the strength of a memory and how efficiently it may be retrieved. The systems at play are multifaceted; on one hand, the dopaminergic mesocorticolimbic system evaluates the rewarding or reinforcing potential of a stimulus, while on the other, the noradrenergic stress response system evaluates the risk of threat, commanding attention, and engaging emotional and physical behavioral responses. Sex-specific patterns in the anatomy and function of the arousal system suggest that sexually divergent therapeutic approaches may be advantageous for neurological disorders involving arousal, learning, and memory. From the lens of the triple network model of psychopathology, we argue that post-traumatic stress disorder and opiate substance use disorder arise from maladaptive learning responses that are perpetuated by hyperarousal of the salience network. We present evidence that catecholamine-modulated learning and stress-responsive circuitry exerts substantial influence over the salience network and its dysfunction in stress-related psychiatric disorders, and between the sexes. We discuss the therapeutic potential of targeting the endogenous cannabinoid system; a ubiquitous neuromodulator that influences learning, memory, and responsivity to stress by influencing catecholamine, excitatory, and inhibitory synaptic transmission. Relevant preclinical data in male and female rodents are integrated with clinical data in men and women in an effort to understand how ideal treatment modalities between the sexes may be different.

The Locus Coeruleus- Norepinephrine System in Stress and Arousal: Unraveling Historical, Current, and Future Perspectives.

Arousal may be understood on a spectrum, with excessive sleepiness, cognitive dysfunction, and inattention on one side, a wakeful state in the middle, and hypervigilance, panic, and psychosis on the other side. However, historically, the concepts of arousal and stress have been challenging to define as measurable experimental variables. Divergent efforts to study these subjects have given rise to several disciplines, including neurobiology, neuroendocrinology, and cognitive neuroscience. We discuss technological advancements that chronologically led to our current understanding of the arousal system, focusing on the multifaceted nucleus locus coeruleus. We share our contemporary perspective and the hypotheses of others in the context of our current technological capabilities and future developments that will be required to move forward in this area of research.

BKCa (Slo) Channel Regulates Mitochondrial Function and Lifespan in Drosophila melanogaster.

BKCa channels, originally discovered in Drosophila melanogaster as slowpoke (slo), are recognized for their roles in cellular and organ physiology. Pharmacological approaches implicated BKCa channels in cellular and organ protection possibly for their ability to modulate mitochondrial function. However, the direct role of BKCa channels in regulating mitochondrial structure and function is not deciphered. Here, we demonstrate that BKCa channels are present in fly mitochondria, and slo mutants show structural and functional defects in mitochondria. slo mutants display an increase in reactive oxygen species and the modulation of ROS affected their survival. We also found that the absence of BKCa channels reduced the lifespan of Drosophila, and overexpression of human BKCa channels in flies extends life span in males. Our study establishes the presence of BKCa channels in mitochondria of Drosophila and ascertains its novel physiological role in regulating mitochondrial structural and functional integrity, and lifespan.

Single-Cell Glia and Neuron Gene Expression in the Central Amygdala in Opioid Withdrawal Suggests Inflammation With Correlated Gut Dysbiosis.

Drug-seeking in opioid dependence is due in part to the severe negative emotion associated with the withdrawal syndrome. It is well-established that negative emotional states emerge from activity in the amygdala. More recently, gut microflora have been shown to contribute substantially to such emotions. We measured gene expression in single glia and neurons gathered from the amygdala using laser capture microdissection and simultaneously measured gut microflora in morphine-dependent and withdrawn rats to investigate drivers of negative emotion in opioid withdrawal. We found that neuroinflammatory genes, notably Tnf, were upregulated in the withdrawal condition and that astrocytes, in particular, were highly active. We also observe a decreased Firmicutes to Bacteroides ratio in opioid withdrawal indicating gut dysbiosis. We speculate that these inflammatory and gut microflora changes contribute to the negative emotion experienced in opioid withdrawal that motivates dependence.

Endocannabinoids, stress signaling, and the locus coeruleus-norepinephrine system.

The endocannabinoid (eCB) system has been implicated in a variety of physiological functions due to abundant expression of its receptors and endogenous ligands in the central nervous system. Substantial progress has been made in understanding how the eCB system influences the brain norepinephrine (NE) system, an important neurochemical target in the continued development of new therapies for stress-induced psychiatric disorders. We, and others, have characterized the neuroanatomical, biochemical and pharmacological effects of cannabinoid receptor modulation on brain noradrenergic circuitry and defined how molecular elements of the eCB system are positioned to directly impact the locus coeruleus (LC)-prefrontal cortex pathway, a neural circuit well recognized for contributing to symptoms of hyperarousal, a key pathophysiological feature of stress-related disorders. We also described molecular and electrophysiological properties of LC noradrenergic neurons and NE release in the medial prefrontal cortex under conditions of cannabinoid type 1 receptor deletion. Finally, we identified how stress influences cannabinoid modulation of the coeruleo-cortical pathway. A number of significant findings emerged from these studies that will be summarized in the present review and have important implications for clinical studies targeting the eCB system in the treatment of stress-induced psychiatric disorders.

Localization of amyloid beta peptides to locus coeruleus and medial prefrontal cortex in corticotropin releasing factor overexpressing male and female mice.

A culmination of evidence from the literature points to the Locus Coeruleus (LC)-Norepinephrine system as an underappreciated and understudied area of research in the context of Alzheimer's Disease (AD). Stress is a risk factor for developing AD, and is supported by multiple clinical and preclinical studies demonstrating that amplification of the stress system disrupts cellular and molecular processes at the synapse, promoting the production and accumulation of the amyloid beta (Aß42) peptide. Stress-induced activation of the LC is mediated by corticotropin releasing factor (CRF) and CRF receptors exhibit sex-biased stress signaling. Sex differences are evident in the neurochemical, morphological and molecular regulation of LC neurons by CRF, providing a compelling basis for the higher prevalence of stress-related disorders such as AD in females. In the present study, we examined the cellular substrates for interactions between Aß and tyrosine hydroxylase a marker of noradrenergic somatodendritic processes in the LC, and Dopamine-ß-Hydroxylase (DßH) in the infralimbic medial prefrontal cortex (ILmPFC) in mice conditionally overexpressing CRF in the forebrain (CRFOE) under a Doxycycline (DOX) regulated tetO promoter. CRFOE was sufficient to elicit a redistribution of Aß peptides in the somatodendritic processes of the LC of male and female transgenic mice, without altering total Aß42 protein expression levels. DOX treated groups exhibited lysosomal compartments with apparent lipofuscin and abnormal morphology, indicating potential dysfunction of these Aß42-clearing compartments. In female DOX treated groups, swollen microvessels with lipid-laden vacuoles were also observed, a sign of blood-brain-barrier dysfunction. Finally, sex differences were observed in the prefrontal cortex, as females responded to DOX treatment with increased frequency of co-localization of Aß42 and DßH in noradrenergic axon terminals compared to vehicle treated controls, while male groups showed no significant changes. We hypothesize that the observed sex differences in Aß42 distribution in this model of CRF hypersignaling is based on increased responsivity of female rodent CRFR1 in the LC. Aß42 production is enhanced during increased neuronal activation, therefore, the excitation of DOX treated female CRFOE LC neurons projecting to the mPFC may exhibit more frequent co-localization with Aß due to increased neuronal activity of noradrenergic neurons.

Single prolonged stress PTSD model triggers progressive severity of anxiety, altered gene expression in locus coeruleus and hypothalamus and effected sensitivity to NPY.

PTSD is heterogeneous disorder that can be long lasting and often has delayed onset following exposure to a traumatic event. Therefore, it is important to take a staging approach to evaluate progression of biological mechanisms of the disease. Here, we begin to evaluate the temporal trajectory of changes following exposure to traumatic stressors in the SPS rat PTSD model. The percent of animals displaying severe anxiety on EPM increased from 17.5% at one week to 57.1% two weeks after SPS stressors, indicating delayed onset or progressive worsening of the symptoms. The LC displayed prolonged activation, and dysbalance of the CRH/NPY systems, with enhanced CRHR1 gene expression, coupled with reduced mRNAs for NPY and Y2R. In the mediobasal hypothalamus, increased CRH mRNA levels were sustained, but there was a flip in alterations of HPA regulatory molecules, GR and FKBP5 and Y5 receptor at two weeks compared to one week. Two weeks after SPS, intranasal NPY at 300 µg/rat, but not 150 µg which was effective after one week, reversed SPS triggered elevated anxiety. It also reversed SPS elicited depressive/despair symptoms and hyperarousal. Overall, the results reveal time-dependent progression in development of anxiety symptoms and molecular impairments in gene expression for CRH and NPY systems in LC and mediobasal hypothalamus by SPS. With longer time afterwards only a higher dose of NPY was effective in reversing behavioral impairments triggered by SPS, indicating that therapeutic approaches should be adjusted according to the degree of biological progression of the disorder.