To date, there is no cure or effective treatment for Alzheimer's disease (AD), a chronic neurodegenerative condition that affects memory, language, and behavior. AD is characterized by neuroinflammation, accumulation of brain amyloid-beta (Aβ) oligomers and neurofibrillary tangles, increased neuronal apoptosis, and loss of synaptic function. Promoting regular exercise and a diet containing polyphenols are effective non-pharmacological approaches that prevent the progression of neurodegenerative diseases. In this study, we measured various conformational toxic species of Aβ and markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection after 5 months of exercise training (ET), resveratrol (Resv) treatment, or combination treatment in the 3xTg-AD mouse model of AD. Our main results indicate that Resv decreased neuroinflammation and accumulation of Aβ oligomers, increased levels of neurotrophins, synaptic markers, silent information regulator, and decreased markers of apoptosis, autophagy, endolysosomal degradation and ubiquitination in the brains of 3xTg-AD mice. ET improved some markers related to neuroprotection, but when combined with Resv treatment, the benefits achieved were as effective as Resv treatment alone. Our results show that the neuroprotective effects of Resv, ET or Resv and ET are associated with reduced toxicity of Aβ oligomers, suppression of neuronal autophagy, decreased apoptosis, and upregulation of key growth-related proteins.

https://www.mdpi.com/1422-0067/21/19/7337/pdf

Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer’s Disease

The vast majority of patients with advanced breast cancer present skeletal complications that severely compromise their quality of life Breast cancer cells are characterized by a strong tropism to the bone niche After engraftment and colonization of bone, breast cancer cells interact with native bone cells to hinder the normal bone remodeling process and establish an osteolytic "metastatic vicious cycle" The sympathetic nervous system has emerged in recent years as an important modulator of breast cancer progression and metastasis, potentiating and accelerating the onset of the vicious cycle and leading to extensive bone degradation Furthermore, sympathetic neurotransmitters and their cognate receptors have been shown to promote several hallmarks of breast cancer, such as proliferation, angiogenesis, immune escape, and invasion of the extracellular matrix In this review, we assembled the current knowledge concerning the complex interactions that take place in the tumor microenvironment, with a special emphasis on sympathetic modulation of breast cancer cells and stromal cells Notably, the differential action of epinephrine and norepinephrine, through either α- or β-adrenergic receptors, on breast cancer progression prompts careful consideration when designing new therapeutic options In addition, the contribution of sympathetic innervation to the formation of bone metastatic foci is highlighted In particular, we address the remarkable ability of adrenergic signaling to condition the native bone remodeling process and modulate the bone vasculature, driving breast cancer cell engraftment in the bone niche Finally, clinical perspectives and developments on the use of β-adrenergic receptor inhibitors for breast cancer management and treatment are discussed

/pdf/sympathetic-activity-in-breast-cancer-and-metastasis-2h2ebn47dc.pdf

Sympathetic activity in breast cancer and metastasis: partners in crime.

Molecular mechanisms and cardiovascular implications of cancer therapy-induced senescence

The fundamental central neural circuits for thermoregulation orchestrate behavioral and autonomic repertoires that maintain body core temperature during thermal challenges that arise from either the ambient or the internal environment. This review summarizes our understanding of the neural pathways within the fundamental thermoregulatory reflex circuitry that comprise the efferent (i.e., beyond thermosensory) control of brown adipose tissue (BAT) and shivering thermogenesis: the motor neuron systems consisting of the BAT sympathetic preganglionic neurons and BAT sympathetic ganglion cells, and the alpha- and gamma-motoneurons; the premotor neurons in the region of the rostral raphe pallidus, and the thermogenesis-promoting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area. Also included are inputs to, and neurochemical modulators of, these efferent neuronal populations that could influence their activity during thermoregulatory responses. Signals of metabolic status can be particularly significant for the energy-hungry thermoeffectors for heat production.

Efferent neural pathways for the control of brown adipose tissue thermogenesis and shivering.

Obesity research progresses in understanding neuronal circuits and adipocyte biology to regulate metabolism. However, the interface of neuro-adipocyte interaction is less studied. We summarize the current knowledge of adipose tissue innervation and interaction with adipocytes and emphasize adipocyte transitions from white to brown adipocytes and vice versa. We further highlight emerging concepts for the differential neuronal regulation of brown/beige versus white adipocyte and the interdependence of both for metabolic regulation.

Sympathetic Innervation of White Adipose Tissue: to Beige or Not to Beige?

Stress and Alzheimer's disease: A senescence link?

The brown adipose tissue (BAT) is a thermogenic organ that plays a major role in energy balance, obesity, and diabetes due to the potent glucose and lipid clearance that fuels its thermogenesis, which is largely mediated via sympathetic nervous system activation. However, thus far there has been little experimental validation of the hypothesis that selective neuromodulation of the sympathetic nerves innervating the BAT is sufficient to elicit thermogenesis in mice. We generated mice expressing blue light-activated channelrhodopsin-2 (ChR2) in the sympathetic nerves innervating the BAT using two different strategies: injecting the BAT of C57Bl/6J mice with AAV6-hSyn-ChR2 (H134R)-EYFP; crossbreeding tyrosine hydroxylase-Cre mice with floxed-stop ChR2-EYFP mice. The nerves in the BAT expressing ChR2 were selectively stimulated with a blue LED light positioned underneath the fat pad of anesthetized mice, while the BAT and core temperatures were simultaneously recorded. Using immunohistochemistry we confirmed the selective expression of EYFP in TH positive nerves fibers. In addition, local optogenetic stimulation of the sympathetic nerves induced significant increase in the BAT temperature followed by an increase in core temperature in mice expressing ChR2, but not in the respective controls. The BAT activation was also paralleled by increased levels of pre-UCP1 transcript. Our results demonstrate that local optogenetic stimulation of the sympathetic nerves is sufficient to elicit BAT and core thermogenesis, thus suggesting that peripheral neuromodulation has the potential to be exploited as an alternative to pharmacotherapies to elicit organ activation and thus ameliorate type 2 diabetes and/or obesity.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.201901361RR

Optogenetic-induced sympathetic neuromodulation of brown adipose tissue thermogenesis.

Late onset, sporadic Alzheimer's disease (AD) accounts for the vast majority of cases Unlike familial AD, the factors that drive the onset of sporadic AD are poorly understood, although aging and stress play a role The early onset/severity of neuropathology observed in most genetic mouse models of AD hampers the study of the role of aging and environmental factors; thus, alternate strategies are necessary to understand the contributions of these factors to sporadic AD We demonstrate that mice acquiring a low social status (subordinate) in a lifelong chronic psychosocial stress (CPS) model, accrue widespread proteomic changes in the frontal/temporal cortex during aging To better understand the significance of these stress-induced changes, we compared the differentially expressed proteins (DEPs) of subordinate mice to those of patients at varying stages of dementia Sixteen and fifteen DEPs upregulated in subordinate mice were also upregulated in patients with mild cognitive impairment (MCI) and AD, respectively Seven of those upregulated proteins (CPE, ERC2, GRIN2B, SLC6A1, SYN1, WFS1) were shared by subordinate mice and patients with MCI or AD Finally, comparison with a spatially detailed transcriptomic database revealed that the superior frontal gyrus and hippocampus had the greatest overlap between mice subjected to lifelong CPS and AD patients Overall, most of the overlapping proteins were functionally associated with enhanced NMDA receptor mediated glutamatergic signaling, an excitotoxicity mechanism known to affect neurodegeneration These findings support the association between stress and AD progression and provide valuable insight into potential early biomarkers and protein mediators of this relationship

Lifelong chronic psychosocial stress induces a proteomic signature of Alzheimer’s Disease in wildtype mice

Tear gases, or chemical demonstration control agents (DCA), were originally created as weapons that could severely disable or kill enemy troops. Though banned in war, these chemicals are still used in domestic policing. Here we review the available scientific literature on tear gas, summarizing findings from animal and environmental studies as well describing data from new human studies. We find a lack of scientific evidence supporting the safety of tear gas, especially regarding its long-term impacts on human health and the environment. Many of the available studies were published decades ago, and do not parse data by variables such as chemical type and exposure time, nor do they account for the diversity of individuals who are exposed to tear gas in real-life situations. Due to the dearth of scientific research and the misinterpretation of some of the available studies, we conclude that a serious reevaluation of chemical DCA safety and more comprehensive exposure follow-up studies are necessary.

Reevaluating tear gas toxicity and safety.

While the U.N. Chemical Weapons Convention bans tear gas and other chemical weapons from use in war, their use is still allowed in domestic policing. Public concern about tear gas utilization increases when social justice protesters are subjected to these chemical demonstration control agents. The history of tear gas utilization by law enforcement in the U.S. is rife with corruption and racist intent. Furthermore, the scientific evidence supporting the safety of tear gas is lacking due to both the misinterpretation of public health studies and the paucity of controlled experiments. We find that the current utilization of tear gas is a threat to public health, free speech, and possibly falls outside of the exception for domestic use. We discuss policy alternatives that include alternative crowd control methods, changes to protocols for tear gas deployment and post-use review, increased regulatory oversight, and the possibility of a complete tear gas ban.

/pdf/tear-gas-safety-and-usage-practices-3q7xbhpgzs.pdf

Carey E. Lyons

Papers

Stress and Alzheimer's disease: A senescence link?

Optogenetic-induced sympathetic neuromodulation of brown adipose tissue thermogenesis.

Lifelong chronic psychosocial stress induces a proteomic signature of Alzheimer’s Disease in wildtype mice

Reevaluating tear gas toxicity and safety.

Tear gas safety and usage practices