The Integrated Stress Response and Phosphorylated Eukaryotic Initiation Factor 2α in Neurodegeneration.

The proposed molecular mechanisms underlying neurodegenerative pathogenesis are varied, precluding the development of effective therapies for these increasingly prevalent disorders. One of the most consistent observations across neurodegenerative diseases is the phosphorylation of eukaryotic initiation factor 2α (eIF2α). eIF2α is a translation initiation factor, involved in cap-dependent protein translation, which when phosphorylated causes global translation attenuation. eIF2α phosphorylation is mediated by 4 kinases, which, together with their downstream signaling cascades, constitute the integrated stress response (ISR). While the ISR is activated by stresses commonly observed in neurodegeneration, such as oxidative stress, endoplasmic reticulum stress, and inflammation, it is a canonically adaptive signaling cascade. However, chronic activation of the ISR can contribute to neurodegenerative phenotypes such as neuronal death, memory impairments, and protein aggregation via apoptotic induction and other maladaptive outcomes downstream of phospho-eIF2α-mediated translation inhibition, including neuroinflammation and altered amyloidogenic processing, plausibly in a feed-forward manner. This review examines evidence that dysregulated eIF2a phosphorylation acts as a driver of neurodegeneration, including a survey of observations of ISR signaling in human disease, inspection of the overlap between ISR signaling and neurodegenerative phenomenon, and assessment of recent encouraging findings ameliorating neurodegeneration using developing pharmacological agents which target the ISR. In doing so, gaps in the field, including crosstalk of the ISR kinases and consideration of ISR signaling in nonneuronal central nervous system cell types, are highlighted.

BACE1 Mediates HIV-Associated and Excitotoxic Neuronal Damage Through an APP-Dependent Mechanism.

HIV-associated neurocognitive disorders (HANDs) share common symptoms with Alzheimer's disease (AD), which is characterized by amyloid-ß (Aß) plaques. Plaques are formed by aggregation of Aß oligomers, which may be the toxic species in AD pathogenesis, and oligomers are generated by cleavage of amyloid precursor protein (APP) by ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 inhibitors reverse neuronal loss and cognitive decline in animal models of AD. Although studies have also found evidence of altered APP processing in HIV+ patients, it is unknown whether increased BACE1 expression or Aß oligomer production is a common neuropathological feature of HAND. Moreover, it is unknown whether BACE1 or APP is involved in the excitotoxic, NMDAR-dependent component of HIV-associated neurotoxicity in vitro Herein, we hypothesize that HIV-associated neurotoxicity is mediated by NMDAR-dependent elevation of BACE1 and subsequent altered processing of APP. Supporting this, we observed elevated levels of BACE1 and Aß oligomers in CNS of male and female HIV+ patients. In a model of HIV-associated neurotoxicity in which rat neurons are treated with supernatants from HIV-infected human monocyte-derived macrophages, we observed NMDAR-dependent elevation of BACE1 protein. NMDA treatment also increased BACE1 and both pharmacological BACE1 inhibition and genetic loss of APP were partially neuroprotective. Moreover, in APP knock-out (APP-/-) mouse neurons, NMDA-induced toxicity was BACE1 independent, indicating that cytotoxicity of BACE1 is dependent upon APP cleavage. Our findings suggest that increased BACE1 and the resultant Aß oligomer production may contribute to HIV-associated neuropathogenesis and inhibition of BACE1 could have therapeutic potential in HANDs.SIGNIFICANCE STATEMENT HIV-associated neurocognitive disorders (HANDs) represent a range of cognitive impairments affecting ∼50% of HIV+ individuals. The specific causes of HAND are unknown, but evidence suggests that HIV-infected macrophage infiltration into the brain may cause neuronal damage. Herein, we show that neurons treated with conditioned media from HIV-infected macrophages have increased expression of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), a protein implicated in Alzheimer's disease pathogenesis. Moreover, inhibition of BACE1 prevented neuronal loss after conditioned media exposure, but had no effect on HIV-associated neurotoxicity in neurons lacking its cleavage target amyloid precursor protein. We also observed increased BACE1 expression in HIV+ patient brain tissue, confirming the potential relevance of BACE1 as a therapeutic target in HANDs.

HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ß-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation.

Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV-associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinase-dependent phosphorylation of the eukaryotic translation initiation factor 2α and enhanced translation of ß-site APP cleaving enzyme-1 (BACE1). In addition, PIs induced ß-amyloid production, indicative of increased BACE1-mediated APP processing, in rodent neuroglial cultures and human APP-expressing Chinese hamster ovary cells. Inhibition of BACE1 activity protected against neuronal damage. Finally, ARVs administered to mice and SIV-infected macaques resulted in neuronal damage and BACE1 up-regulation in the central nervous system. These findings implicate a subset of PIs as potential mediators of neurodegeneration in HIV-associated neurocognitive disorders.

Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders.

Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals have HIV-associated neurocognitive disorders (HAND). Studies of antiretroviral-treated patients have revealed persistent white matter abnormalities including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction because the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance. We hypothesized that myelin changes in HAND are partly due to effects of antiretroviral drugs on oligodendrocyte survival and/or maturation. We showed that primary mouse oligodendrocyte precursor cell cultures treated with therapeutic concentrations of HIV protease inhibitors ritonavir or lopinavir displayed dose-dependent decreases in oligodendrocyte maturation; however, this effect was rapidly reversed after drug removal. Conversely, nucleoside reverse transcriptase inhibitor zidovudine had no effect. Furthermore, in vivo ritonavir administration to adult mice reduced frontal cortex myelin protein levels. Finally, prefrontal cortex tissue from HIV-positive individuals with HAND on cART showed a significant decrease in myelin basic protein compared with untreated HIV-positive individuals with HAND or HIV-negative controls. These findings demonstrate that antiretrovirals can impact myelin integrity and have implications for myelination in juvenile HIV patients and myelin maintenance in adults on lifelong therapy.

Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system.

HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.

Odor identification ability and self-reported upper respiratory symptoms in workers at the post-9/11 World Trade Center site.

UNLABELLED: Following the World Trade Center (WTC) collapse on September 11, 2001, more than 40,000 people were exposed to a complex mixture of inhalable nanoparticles and toxic chemicals. While many developed chronic respiratory symptoms, to what degree olfaction was compromised is unclear. A previous WTC Medical Monitoring and Treatment Program study found that olfactory and nasal trigeminal thresholds were altered by the toxic exposure, but not scores on a 20-odor smell identification test. OBJECTIVES: To employ a well-validated 40-item smell identification test to definitively establish whether the ability to identify odors is compromised in a cohort of WTC-exposed individuals and, if so, whether the degree of compromise is associated with self-reported severity of rhinitic symptoms. METHODS: The University of Pennsylvania Smell Identification Test (UPSIT) was administered to 99 WTC-exposed persons and 99 matched normal controls. The Sino-Nasal Outcomes Test (SNOT-20) was administered to the 99 WTC-exposed persons and compared to the UPSIT scores. RESULTS: The mean (SD) UPSIT scores were lower in the WTC-exposed group than in age-, sex-, and smoking history-matched controls [respective scores: 30.05 (5.08) vs 35.94 (3.76); p = 0.003], an effect present in a subgroup of 19 subjects additionally matched on occupation (p < 0.001). Fifteen percent of the exposed subjects had severe microsmia, but only 3% anosmia. SNOT-20 scores were unrelated to UPSIT scores (r = 0.20; p = 0.11). CONCLUSION: Exposure to WTC air pollution was associated with a decrement in the ability to identify odors, implying that such exposure had a greater influence on smell function than previously realized.

Symbolic gestures and spoken language are processed by a common neural system.

Symbolic gestures, such as pantomimes that signify actions (e.g., threading a needle) or emblems that facilitate social transactions (e.g., finger to lips indicating "be quiet"), play an important role in human communication. They are autonomous, can fully take the place of words, and function as complete utterances in their own right. The relationship between these gestures and spoken language remains unclear. We used functional MRI to investigate whether these two forms of communication are processed by the same system in the human brain. Responses to symbolic gestures, to their spoken glosses (expressing the gestures' meaning in English), and to visually and acoustically matched control stimuli were compared in a randomized block design. General Linear Models (GLM) contrasts identified shared and unique activations and functional connectivity analyses delineated regional interactions associated with each condition. Results support a model in which bilateral modality-specific areas in superior and inferior temporal cortices extract salient features from vocal-auditory and gestural-visual stimuli respectively. However, both classes of stimuli activate a common, left-lateralized network of inferior frontal and posterior temporal regions in which symbolic gestures and spoken words may be mapped onto common, corresponding conceptual representations. We suggest that these anterior and posterior perisylvian areas, identified since the mid-19th century as the core of the brain's language system, are not in fact committed to language processing, but may function as a modality-independent semiotic system that plays a broader role in human communication, linking meaning with symbols whether these are words, gestures, images, sounds, or objects.

Leftward interhemispheric asymmetry of macaque monkey temporal lobe language area homolog is evident at the cytoarchitectural, but not gross anatomic level.

The most marked leftward interhemispheric asymmetry of the human and great ape brain is present in a multisensory association area of the superior temporal gyrus. This cortical region, the planum temporale (part of Brodmann's area 22), has a cytoarchitectural homolog, area Tpt, in Old World monkeys. Reports in non-human primates vary widely in descriptions of area Tpt-associated indices of asymmetry at the gross anatomic level, but such asymmetry has not yet been considered at the cellular level. Here we assessed a mixed sex sample of perfusion-fixed adult macaque monkey brains to determine whether purported interhemispheric asymmetry of Tpt is manifested at the gross anatomic level by consideration of the length of the lateral sulcus. A separate sample was used to consider interhemispheric asymmetry by volumetric assessment of the cytoarchitectural profile of area Tpt. There was no significant hemispheric asymmetry of lateral sulcus length at the gross anatomic level. Previous studies that used endocasts may not have factored in opercularization of the sylvian point, shown here as being pronounced. Conversely, there was a significant leftward volumetric asymmetry of area Tpt at the cytoarchitectural level. Furthermore, the intrahemispheric profile of area Tpt topography was more varied than expected. These results indicate that leftward hemispheric asymmetry of these critical human language areas may have been based on a functional substrate with a long evolutionary history. The leftward cytoarchitectural asymmetry and highly varied topography of Tpt should be factored into investigative approaches that consider this region of the cerebral cortex.

Planum parietale of chimpanzees and orangutans: a comparative resonance of human-like planum temporale asymmetry.

We have previously demonstrated that leftward asymmetry of the planum temporale (PT), a brain language area, was not unique to humans since a similar condition is present in great apes. Here we report on a related area in great apes, the planum parietale (PP). PP in humans has a rightward asymmetry with no correlation to the L>R PT, which indicates functional independence. The roles of the PT in human language are well known while PP is implicated in dyslexia and communication disorders. Since posterior bifurcation of the sylvian fissure (SF) is unique to humans and great apes, we used it to determine characteristics of its posterior ascending ramus, an indicator of the PP, in chimpanzee and orangutan brains. Results showed a human-like pattern of R>L PP (P = 0.04) in chimpanzees with a nonsignificant negative correlation of L>R PT vs. R>L PP (CC = -0.3; P = 0.39). In orangutans, SF anatomy is more variable, although PP was nonsignificantly R>L in three of four brains (P = 0.17). We have now demonstrated human-like hemispheric asymmetry of a second language-related brain area in great apes. Our findings persuasively support an argument for addition of a new component to the comparative neuroanatomic complex that defines brain language or polymodal communication areas. PP strengthens the evolutionary links that living great apes may offer to better understand the origins of these progressive parts of the brain. Evidence mounts for the stable expression of a neural foundation for language in species that we recently shared a common ancestor with.

Communicating bioastronautics research to students, families and the nation.

The National Space Biomedical Research Institute (NSBRI) is supporting the National Aeronautics and Space Administration's (NASA) education mission through a comprehensive Education and Public Outreach Program (EPOP) that communicates the excitement and significance of space biology to schools, families, and lay audiences. The EPOP is comprised of eight academic institutions: Baylor College of Medicine, Massachusetts Institute of Technology, Morehouse School of Medicine, Mount Sinai School of Medicine, Texas A&M University, University of Texas Medical Branch Galveston, Rice University, and the University of Washington. This paper describes the programs and products created by the EPOP to promote space life science education in schools and among the general public. To date, these activities have reached thousands of teachers and students around the US and have been rated very highly.

Evolution of the brainstem orofacial motor system in primates: a comparative study of trigeminal, facial, and hypoglossal nuclei.

The trigeminal motor (Vmo), facial (VII), and hypoglossal (XII) nuclei of the brainstem comprise the final common output for neural control of most orofacial muscles. Hence, these cranial motor nuclei are involved in the production of adaptive behaviors such as feeding, facial expression, and vocalization. We measured the volume and Grey Level Index (GLI) of Vmo, VII, and XII in 47 species of primates and examined these nuclei for scaling patterns and phylogenetic specializations. Allometric regression, using medulla volume as an independent variable, did not reveal a significant difference between strepsirrhines and haplorhines in the scaling of Vmo volume. In addition, correlation analysis using independent contrasts did not find a relationship between Vmo size or GLI and the percent of leaves in the diet. The scaling trajectory of VII volume, in contrast, differed significantly between suborders. Great ape and human VII volumes, furthermore, were significantly larger than predicted by the haplorhine regression. Enlargement of VII in these taxa may reflect increased differentiation of the facial muscles of expression and greater utilization of the visual channel in social communication. The independent contrasts of VII volume and GLI, however, were not correlated with social group size. To examine whether the human hypoglossal motor system is specialized to control the tongue for speech, we tested human XII volume and GLI for departures from nonhuman haplorhine prediction lines. Although human XII volumes were observed above the regression line, they did not exceed prediction intervals. Of note, orang-utan XII volumes had greater residuals than humans. Human XII GLI values also did not differ from allometric prediction. In sum, these findings indicate that the cranial orofacial motor nuclei evince a mosaic of phylogenetic specializations for innervation of the facial muscles of expression in the context of a generally conservative scaling relationship with respect to medulla size.

Microvascular transplantation of tracheal allografts model in the canine.

The inability to reconstruct extensive and often life-threatening tracheal defects is a clinical dilemma. The objective of this study was to achieve microvascular revascularization and transplantation of long-segment circumferential tracheal allografts in a canine model. Fifteen mongrel dogs were randomly assigned to 5 treatment groups. Twelve dogs underwent an excision of an 8-cm tracheal segment followed by transplantation and microvascular revascularization of an 8-cm cervical trachea allograft. Group 1 (n = 4) was treated with 10 mg/kg per day of cyclosporin A (CsA) and 7.5 mg/kg per day of mycophenolate mofetil (MM). Group 2 (n = 4) was treated with 5 mg/kg per day of CsA and 7.5 mg/kg per day of MM. Group 3 (n = 4) was treated with 2.5 mg/kg per day of CsA and 7.5 mg/kg per day of MM. Group 4 (n = 2) underwent an autograft tracheal transplant and received postoperative 2.5 mg/kg perday of CsA and 7.5 mg/kg per day of MM. Group 5 (n = 1) did not undergo surgery, but received postoperative 2.5 mg/kg per day of CsA and 7.5 mg/kg per day of MM. The animals were maintained for a duration of 30 days, during which time the graft was assessed by routine endoscopic examination and tracheal biopsies. Ex vivo, tracheal autografts were examined grossly for graft healing and microscopically for histologic architecture. The mean survival times were 13.25 days (group 1), 16 days (group 2), and 20 days (group 3). There was 1 early allograft failure secondary to microvascular thrombosis, and there were 4 delayed failures secondary to postoperative wound infections. Five dogs were euthanized before the end of the 30-day observation period because of failure to thrive or hypocalcemic tetany. None of the dogs in the study demonstrated endoscopic or histologic evidence of rejection before euthanasia. Postmortem examination of the surviving dogs demonstrated normal histologic architecture without evidence of rejection. For the first time, we have achieved allotransplantation of long tracheal segments based on the cranial thyroid artery and internal jugular vein. Minimal systemic immunosuppression appears to be associated with a higher survival rate and a lower complication rate.

Variability of Broca's area homologue in African great apes: implications for language evolution.

The cortical circuits subserving neural processing of human language are localized to the inferior frontal operculum and the posterior perisylvian region. Functional language dominance has been related to anatomical asymmetry of Broca's area and the planum temporale. The evolutionary history of these asymmetric patterns, however, remains obscure. Although testing of hypotheses about the evolution of language areas requires comparison to homologous regions in the brains of our closest living relatives, the great apes, to date little is known about normal interindividual variation of these regions in this group. Here we focus on Brodmann's area 44 in African great apes (Pan troglodytes and Gorilla gorilla). This area corresponds to the pars opercularis of the inferior frontal gyrus (IFG), and has been shown to exhibit both gross and cytoarchitectural asymmetries in humans. We calculated frequencies of sulcal variations and mapped the distribution of cytoarchitectural area 44 to determine whether its boundaries occurred at consistent macrostructural landmarks. A considerable amount of variation was found in the distribution of the inferior frontal sulci among great ape brains. The inferior precentral sulcus in particular was often bifurcated, which made it impossible to determine the posterior boundary of the pars opercularis. In addition, the distribution of Brodmann's area 44 showed very little correspondence to surface anatomy. We conclude that gross morphologic patterns do not offer substantive landmarks for the measurement of Brodmann's area 44 in great apes. Whether or not Broca's area homologue of great apes exhibits humanlike asymmetry can only be resolved through further analyses of microstructural components.

Microvascular transfer of long tracheal autograft segments in the canine model.

OBJECTIVE: The reconstruction of long segment tracheal defects represents an unsolved clinical dilemma. Prior attempts to directly revascularize tracheal segments have been unsuccessful. The objective of this study was to evaluate orthotopic autotransplantation of revascularized long tracheal segments in the canine model. METHODS: Ten randomly selected mongrel dogs underwent excision, orthotopic reimplantation, and microvascular revascularization of a long segment (8.0 cm) of cervical trachea. The cranial thyroid artery and the internal jugular vein served as the vascular supply for the tracheal segment. The animals were maintained for a period of 30 days during which time graft viability was measured by routine endoscopic assessment and tracheal biopsies. Ex vivo, tracheal autografts were examined grossly for graft healing an d microscopicallyfor histologic architecture. RESULTS: Seven of 10 dogs survived the predetermined 30-day postoperative study period without complications. Postmortem examination demonstrated that 7 dogs had healed tracheal autograft segments with normal histologic architecture, 2 dogs sustained a postoperative wound infection and tracheal dehiscence, and 1 dog sustained a fatal postoperative hematoma. CONCLUSIONS: For the first time, we have demonstrated direct revascularization of long segment tracheal autografts in the dog model using the cranial thyroid artery and internal jugular vein as the vascular supply.