RÉSUMÉ
There is a critical need to generate age- and sex-specific survival curves to characterize chronological aging consistently across nonhuman primates (NHP) used in biomedical research. Accurate measures of chronological aging are essential for inferences into genetic, demographic, and physiological variables driving differences in NHP lifespan within and between species. Understanding NHP lifespans is relevant to public health because unraveling the demographic, molecular, and clinical bases of health across the life course in translationally relevant NHP species is fundamentally important to the study of human aging. Data from more than 110,000 captive individual NHP were contributed by 15 major research institutions to generate sex-specific Kaplan-Meier survival curves using uniform methods in 12 translational aging models: Callithrix jacchus (common marmoset), Chlorocebus aethiops sabaeus (vervet/African green), Macaca fascicularis (cynomolgus macaque), M. fuscata (Japanese macaque), M. mulatta (rhesus macaque), M. nemestrina (pigtail macaque), M. radiata (bonnet macaque), Pan troglodytes spp. (chimpanzee), Papio hamadryas spp. (baboon), Plecturocebus cupreus (coppery titi monkey), Saguinus oedipus (cotton-top tamarin), and Saimiri spp. (squirrel monkey). After employing strict inclusion criteria, primary analysis results are based on 12,269 NHP that survived to adulthood and died of natural/health-related causes. A secondary analysis was completed for 32,616 NHP that died of any cause. For the primary analyses, we report ages of 25th, 50th, 75th, and 85th percentiles of survival, maximum observed ages, rates of survivorship, and sex-based differences captured by quantile regression models and Kolmogorov-Smirnov tests. Our findings show a pattern of reduced male survival among catarrhines (African and Asian primates), especially macaques, but not platyrrhines (Central and South American primates). For many species, median lifespans were lower than previously reported. An important consideration is that these analyses may offer a better reflection of healthspan than lifespan. Captive NHP used in research are typically euthanized for humane welfare reasons before their natural end of life, often after diagnosis of their first major disease requiring long-term treatment with reduced quality of life (e.g., endometriosis, cancer, osteoarthritis). Supporting the idea that these data are capturing healthspan, for several species typical age at onset of chronic disease is similar to the median lifespan estimates. This data resource represents the most comprehensive characterization of sex-specific lifespan and age-at-death distributions for 12 biomedically relevant species, to date. The results clarify the relationships among NHP ages and will provide a valuable resource for the aging research community, improving human-NHP age equivalencies, informing investigators of the expected survival rates of NHP assigned to studies, providing a metric for comparisons in future studies, and contributing to our understanding of the factors that drive lifespan differences within and among species.
RÉSUMÉ
Sarcopenia is a progressive disorder characterized by age-related loss of skeletal muscle mass and function. Although significant progress has been made over the years to identify the molecular determinants of sarcopenia, the precise mechanisms underlying the age-related loss of contractile function remains unclear. Advances in "omics" technologies, including mass spectrometry-based proteomic and metabolomic analyses, offer great opportunities to better understand sarcopenia. Herein, we performed mass spectrometry-based analyses of the vastus lateralis from young, middle-aged, and older rhesus monkeys to identify molecular signatures of sarcopenia. In our proteomic analysis, we identified proteins that change with age, including those involved in adenosine triphosphate and adenosine monophosphate metabolism as well as fatty acid beta oxidation. In our untargeted metabolomic analysis, we identified metabolites that changed with age largely related to energy metabolism including fatty acid beta oxidation. Pathway analysis of age-responsive proteins and metabolites revealed changes in muscle structure and contraction as well as lipid, carbohydrate, and purine metabolism. Together, this study discovers new metabolic signatures and offers new insights into the molecular mechanisms underlying sarcopenia for the evaluation and monitoring of a therapeutic treatment of sarcopenia.
RÉSUMÉ
Studies looking at individual variability in cognition have increased in recent years. We followed 43 marmosets (21 males, 22 females) from infancy to young adulthood. At 3-months old, marmosets were trained to touch a rewarded stimulus. At 9-, 15-, and 21-months old, they were given visual discrimination and cognitive bias tests, and urine samples were collected to examine hormone levels. Marmosets were significantly more successful learners at 15 months than 9 months. Individuals who were more successful learners at 9 months were also more successful at 15 months, with more male learners than expected at 15 months. At 9 months, learning success was associated with higher cortisol levels. At 15 months, males with higher estradiol levels were more successful learners, whereas at 21 months, females with higher estradiol and cortisol levels tended to be less successful learners and more pessimistic. Nine months, therefore, appears to be an important developmental timepoint for acquiring cognitive control, which has developed by 15 months. Steroids may have differential effects on each sex, with complex interactions between gonadal and adrenal hormones having an influence on cognitive function over the lifespan. This longitudinal study offers new insight into cognition, including its development and biological underpinnings.
Sujet(s)
Callithrix , Hydrocortisone , Animaux , Femelle , Mâle , Nourrisson , Humains , Jeune adulte , Adulte , Callithrix/psychologie , Études longitudinales , Cognition , OestradiolRÉSUMÉ
Parents' psychological stress during the perinatal and neonatal periods continues to increase in an environment of declining birthrates, aging populations, and shrinking family sizes. The increase in child abuse and neglect cases, most likely by inexperienced and insufficiently knowledgeable parents, necessitates education on childcare and intervention techniques in nursing and midwifery training. In particular, attachment formation early in life between mother and infant is crucial. To accurately teach sensitive and comprehensive information on intervention techniques for mother-child attachment formation, realistic videos, and educational materials are necessary. Although pseudoeducational materials are available, they might be limited in explaining complex realism, particularly to support breastfeeding that involves both parents and child and that encourages interaction between the two. In a previous study in a common marmoset (Callithrix jacchus) model, we experimentally controlled infant feeding and nurturing through 24 h of constant sensing and collected 1 month of quantitative data on psychological indices that possibly translated to psychological development. Age-dependent dynamic visualization of these data by multivariate analyses inferred causal relationships between early parental feeding and psychobiological rhythm formation. In the same primate model, we identified a spontaneous case of breastfeeding failure in which the father inhibited his neonatal infant's feeding and the mother appeared to abandon nurturing, leading to clinically significant weight loss in the infant. Thus, we explored intervention techniques to promote mother-infant interaction. The mother was trained to allow the infant to spontaneously explore her breast. Initially, the mother refused to display the feeding pose potentially due to pain associated with breast engorgement. Massage was used to soften the breast and feeding was reintroduced. We hypothesize that activation of instinctive attachment formation mechanisms by encouraging spontaneity in each parent and child is the key to successful feeding intervention.
Sujet(s)
Allaitement naturel , Mères , Animaux , Femelle , Humains , Nouveau-né , Mâle , Callithrix , Pères , Mères/psychologie , Analyse multifactorielleRÉSUMÉ
OBJECTIVE: Exposure of neonatal macaques to the antiseizure medications phenobarbital and midazolam (PbM) causes widespread apoptotic death of neurons and oligodendrocytes. We studied behavior and neurocognitive performance in 12 to 24 month-old macaques treated as neonates with PbM. METHODS: A total of 14 monkeys received phenobarbital and midazolam over 24 hours under normothermia (n = 8) or mild hypothermia (n = 6). Controls (n = 8) received no treatment. Animals underwent testing in the human intruder paradigm at ages 12 and 18 months, and a 3-step stimulus discrimination task at ages 12, 18, and 24 months. RESULTS: Animals treated with PbM displayed lower scores for environmental exploration, and higher scores for locomotion and vocalizations compared with controls. Combined PbM and hypothermia resulted in lower scores for aggression and vigilance at 12 months compared with controls and normothermic PbM animals. A mixed-effects generalized linear model was used to test for differences in neurocognitive performance between the control and PbM groups in the first step of the stimulus discrimination task battery (shape center baited to shape center non-baited). The odds of passing this step differed by group (p = 0.044). At any given age, the odds of passing for a control animal were 9.53-fold (95% CI 1.06-85) the odds for a PbM animal. There was also evidence suggesting a higher learning rate in the shape center non-baited for the control relative to the PbM group (Cox model HR 2.13, 95% CI 1.02-4.43; p = 0.044). INTERPRETATION: These findings demonstrate that a 24-hour-long neonatal treatment with a clinically relevant combination of antiseizure medications can have long-lasting effects on behavior and cognition in nonhuman primates. ANN NEUROL 2023.
RÉSUMÉ
Sarcopenia is a progressive disorder characterized by age-related loss of skeletal muscle mass and function. Although significant progress has been made over the years to identify the molecular determinants of sarcopenia, the precise mechanisms underlying the age-related loss of contractile function remains unclear. Advances in omics technologies, including mass spectrometry-based proteomic and metabolomic analyses, offer great opportunities to better understand sarcopenia. Herein, we performed mass spectrometry-based analyses of the vastus lateralis from young, middle-aged, and older rhesus monkeys to identify molecular signatures of sarcopenia. In our proteomic analysis, we identified numerous proteins that change with age, including those involved in adenosine triphosphate and adenosine monophosphate metabolism as well as fatty acid beta oxidation. In our untargeted metabolomic analysis, we identified multiple metabolites that changed with age largely related to energy metabolism including fatty acid beta oxidation. Pathway analysis of age-responsive proteins and metabolites revealed changes in muscle structure and contraction as well as lipid, carbohydrate, and purine metabolism. Together, this study discovers new metabolic signatures and offer new insights into the molecular mechanism underlying sarcopenia for the evaluation and monitoring of therapeutic treatment of sarcopenia.
RÉSUMÉ
Lower urinary tract (LUT) dysfunction is prevalent in the elderly population, and clinical manifestations include urinary retention, incontinence, and recurrent urinary tract infections. Age-associated LUT dysfunction is responsible for significant morbidity, compromised quality of life, and rising healthcare costs in older adults, but its pathophysiology is not well understood. We aimed to investigate the effects of aging on LUT function by urodynamic studies and metabolic markers in non-human primates. Adult (n = 27) and aged (n = 20) female rhesus macaques were evaluated by urodynamic and metabolic studies. Cystometry showed detrusor underactivity (DU) with increased bladder capacity and compliance in aged subjects. Metabolic syndrome indicators were present in the aged subjects, including increased weight, triglycerides, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and high sensitivity C-reactive protein (hsCRP), whereas aspartate aminotransferase (AST) was unaffected and the AST/ALT ratio reduced. Principal component analysis and paired correlations showed a strong association between DU and metabolic syndrome markers in aged primates with DU but not in aged primates without DU. The findings were unaffected by prior pregnancies, parity, and menopause. Our findings provide insights into possible mechanisms for age-associated DU and may guide new strategies to prevent and treat LUT dysfunction in older adults.
Sujet(s)
Syndrome métabolique X , Hypoactivité vésicale , Sujet âgé , Animaux , Femelle , Humains , Syndrome métabolique X/complications , Macaca mulatta , Qualité de vie , Vessie urinaire , Urodynamique/physiologieRÉSUMÉ
Increased urbanization has decreased children's access to various natural outdoor environments. To counteract this deficiency in early life experiences, we designed four temporary waterslides, each tailored to different city-side park conditions. The waterslides were simple to construct, with frames built from easy-to-attain resources such as bamboo rods from a local forest and simple pipes and joints overlaid by a tarp. Plywood boards, cardboard, and a tarp were used to create a pool at the foot of the slides, which were placed on existing slopes or stairs in each park. Water was continually released down the slide during each 1-2 h event. At each park event, children gathered spontaneously to use the slides and interact socially. No serious accidents occurred during the waterslide trials. To understand how the children used each waterslide, the activity at the waterslides was recorded by video. The minute of the highest activity level at the waterslide was quantitatively analyzed to determine the lines of flow surrounding the waterslide and the mean and maximum speeds attained while using the waterslide.
Sujet(s)
Parcs de loisirs , Socialisation , Humains , Enfant , Forêts , Adaptation physiologiqueRÉSUMÉ
The development of an easy-to-attach electroencephalograph (EEG) would enable its frequent use for the assessment of neurodevelopment and clinical monitoring. In this study, we designed a two-channel EEG headband measurement device that could be used safely and was easily attachable and removable without the need for restraint or electrode paste or gel. Next, we explored the use of this device for neurofeedback applications relevant to education or neurocognitive development. We developed a prototype visual neurofeedback game in which the size of a familiar local mascot changes in the PC display depending on the user's brain wave activity. We tested this application at a local children's play event. Children at the event were invited to experience the game and, upon agreement, were provided with an explanation of the game and support in attaching the EEG device. The game began with a consecutive number visual discrimination task which was followed by an open-eye resting condition and then a neurofeedback task. Preliminary linear regression analyses by the least-squares method of the acquired EEG and age data in 30 participants from 5 to 20 years old suggested an age-dependent left brain lateralization of beta waves at the neurofeedback stage (p = 0.052) and of alpha waves at the open-eye resting stage (p = 0.044) with potential involvement of other wave bands. These results require further validation.
Sujet(s)
Rétroaction neurologique , Adolescent , Adulte , Encéphale , Cortex cérébral , Enfant , Développement de l'enfant , Enfant d'âge préscolaire , Électroencéphalographie/méthodes , Humains , Rétroaction neurologique/méthodes , Repos , Jeune adulteRÉSUMÉ
Metabolic syndrome increases risk of complicating co-morbidities. Current clinical indicators reflect established metabolic impairment, preventing earlier intervention strategies. Here we show that circulating sphingolipids are altered in the very early stages of insulin resistance development. The study involved 16 paired overweight but healthy monkeys, one-half of which spontaneously developed metabolic syndrome over the course of 2 years. Importantly, animals did not differ in adiposity and were euglycemic throughout the study period. Using mass spectrometry, circulating sphingolipids, including ceramides and sphingomyelins, were detected and quantified for healthy and impaired animals at both time points. At time of diagnosis, several ceramides were significantly different between healthy and impaired animals. Correlation analysis revealed differences in the interactions among ceramides in impaired animals at diagnosis and pre-diagnosis when animals were clinically indistinguishable from controls. Furthermore, correlations between ceramides and early-stage markers of insulin resistance, diacylglycerols and non-esterified fatty acids, were distinct for healthy and impaired states. Regression analysis identifies coordinated changes in lipid handling across lipid classes as animals progress from healthy to insulin resistant. Correlations between ceramides and the adipose-derived adipokine adiponectin were apparent in healthy animals but not in the metabolically impaired animals, even in advance of loss in insulin sensitivity. These data suggest that circulating ceramides are clinically relevant in identifying disease risk independent of differences in adiposity, and may be important in devising preventative strategies.
Sujet(s)
Insulinorésistance , Syndrome métabolique X , Animaux , Céramides , Macaca mulatta , Syndrome métabolique X/étiologie , Obésité/métabolisme , SphingolipidesRÉSUMÉ
Context: Ovarian estradiol supports female sexual behavior and metabolic function. While ovariectomy (OVX) in rodents abolishes sexual behavior and enables obesity, OVX in nonhuman primates decreases, but does not abolish, sexual behavior, and inconsistently alters weight gain. Objective: We hypothesize that extra-ovarian estradiol provides key support for both functions, and to test this idea, we employed aromatase inhibition to eliminate extra-ovarian estradiol biosynthesis and diet-induced obesity to enhance weight gain. Methods: Thirteen adult female marmosets were OVX and received (1) estradiol-containing capsules and daily oral treatments of vehicle (E2; nâ =â 5); empty capsules and daily oral treatments of either (2) vehicle (VEH, 1 mL/kg, nâ =â 4), or (3) letrozole (LET, 1 mg/kg, nâ =â 4). Results: After 7 months, we observed robust sexual receptivity in E2, intermediate frequencies in VEH, and virtually none in LET females (Pâ =â .04). By contrast, few rejections of male mounts were observed in E2, intermediate frequencies in VEH, and high frequencies in LET females (Pâ =â .04). Receptive head turns were consistently observed in E2, but not in VEH and LET females. LET females, alone, exhibited robust aggressive rejection of males. VEH and LET females demonstrated increased % body weight gain (Pâ =â .01). Relative estradiol levels in peripheral serum were E2 >>> VEHâ >â LET, while those in hypothalamus ranked E2â =â VEHâ >â LET, confirming inhibition of local hypothalamic estradiol synthesis by letrozole. Conclusion: Our findings provide the first evidence for extra-ovarian estradiol contributing to female sexual behavior in a nonhuman primate, and prompt speculation that extra-ovarian estradiol, and in particular neuroestrogens, may similarly regulate sexual motivation in other primates, including humans.
RÉSUMÉ
There is substantial evidence linking the prefrontal cortex (PFC) to a variety of cognitive abilities, with adolescence being a critical period in its development. In the current study, we investigated the neural basis of differences in learning in pre-adolescent common marmosets. At 8 months old, marmosets were given anatomical and resting state MRI scans (n = 24). At 9 months old, association learning and inhibitory control was tested using a 'go/no go' visual discrimination (VD) task. Marmosets were grouped into 'learners' (n = 12) and "non-learners" (n = 12), and associations between cognitive performance and sub-regional PFC volumes, as well as PFC connectivity patterns, were investigated. "Learners" had significantly (p < 0.05) larger volumes of areas 11, 25, 47 and 32 than 'non-learners', although 'non-learners' had significantly larger volumes of areas 24a and 8 v than "learners". There was also a significant correlation between average % correct responses to the 'punished' stimulus and volume of area 47. Further, 'non-learners' had significantly greater global PFC connections, as well as significantly greater numbers of connections between the PFC and basal ganglia, cerebellum and hippocampus, compared to 'learners'. These results suggest that larger sub-regions of the orbitofrontal cortex and ventromedial PFC, as well more refined PFC connectivity patterns to other brain regions associated with learning, may be important in successful response inhibition. This study therefore offers new information on the neurodevelopment of individual differences in cognition during pre-adolescence in non-human primates.
Sujet(s)
Callithrix , Cortex préfrontal , Animaux , Encéphale , Apprentissage , Imagerie par résonance magnétique , Voies nerveuses/physiologie , Cortex préfrontal/imagerie diagnostiqueRÉSUMÉ
Common marmoset fathers are highly involved in care of their infants. However, variability exists in their response to infant behavior even in paternally experienced fathers. Using infant distress cries as a motivation test, we investigated: 1. the differences in paternally experienced fathers' motivation to search for the infant vocalization stimuli; 2. the relationship between a father's motivation to search for the source of the infant cries and testosterone levels; and 3. if there is a rapid steroidogenesis pathway leading to increased testosterone and estradiol in the peripheral circulation. Only 44% of the paternally experienced fathers showed a high frequency of searching for the source of the infant distress cries. Through the use of multisteroid analysis, we found high responsive fathers had significantly higher levels of progesterone and testosterone in response to infant distress cries compared to a control stimulus with progesterone and androstenedione correlating with testosterone, while no differences were seen in low responders. The frequency to search for the infant stimuli was positively correlated with higher testosterone compared to control vocal levels. These results suggest that searching for the source of infant cries represents a motivation behavior for fathers that is activated by testosterone and reflects rapid circulating testosterone.
Sujet(s)
Callithrix , Comportement paternel , Androgènes/métabolisme , Animaux , Callithrix/physiologie , Pères , Humains , Nourrisson , Mâle , Motivation , Comportement paternel/physiologie , Progestérone/métabolisme , Testostérone/métabolismeRÉSUMÉ
The loss of skeletal muscle function with age, known as sarcopenia, significantly reduces independence and quality of life and can have significant metabolic consequences. Although exercise is effective in treating sarcopenia it is not always a viable option clinically, and currently, there are no pharmacological therapeutic interventions for sarcopenia. Here, we show that chronic treatment with pan-adiponectin receptor agonist AdipoRon improved muscle function in male mice by a mechanism linked to skeletal muscle metabolism and tissue remodeling. In aged mice, 6 weeks of AdipoRon treatment improved skeletal muscle functional measures in vivo and ex vivo. Improvements were linked to changes in fiber type, including an enrichment of oxidative fibers, and an increase in mitochondrial activity. In young mice, 6 weeks of AdipoRon treatment improved contractile force and activated the energy-sensing kinase AMPK and the mitochondrial regulator PGC-1a (peroxisome proliferator-activated receptor gamma coactivator one alpha). In cultured cells, the AdipoRon induced stimulation of AMPK and PGC-1a was associated with increased mitochondrial membrane potential, reorganization of mitochondrial architecture, increased respiration, and increased ATP production. Furthermore, the ability of AdipoRon to stimulate AMPK and PGC1a was conserved in nonhuman primate cultured cells. These data show that AdipoRon is an effective agent for the prevention of sarcopenia in mice and indicate that its effects translate to primates, suggesting it may also be a suitable therapeutic for sarcopenia in clinical application.
Sujet(s)
Adiponectine , Récepteurs à l'adiponectine , Adiponectine/métabolisme , Animaux , Mâle , Souris , Muscles squelettiques/métabolisme , Pipéridines , Primates , Qualité de vie , Récepteurs à l'adiponectine/métabolismeRÉSUMÉ
Insulin is a peptide hormone that is secreted by the ß cells of the pancreas and is essential to the metabolism of carbohydrates, fats, and proteins in the body. The marmoset insulin peptide is not homologous with human insulin and therefore commonly available assays do not work for this species. Due to the increasing popularity of marmoset research, a simple, specific assay for the quantitation of marmoset insulin is needed. This study aimed to develop and validate a bottom-up proteomic workflow with trypsin digestion and analysis using LC coupled with triple quadrupole mass spectrometry (LC-MS/MS). Marmoset serum proteins were subjected to denaturation, reduction, and enzymatic cleavage to extract a unique, 7 amino acid peptide for quantitation of marmoset insulin. Resolution of the peptide was achieved by LC-MS/MS using electrospray ionization operating in positive mode. Calibration was achieved by aliquot dilution of fully synthetic marmoset insulin tryptic peptide into macaque serum. A stable-isotope labeled (13C, 15N) synthetic marmoset insulin tryptic peptide was used as internal standard. The assay was fully validated according to bioanalytical method validation guidelines for linearity, precision, and dilution linearity using purified marmoset insulin. The limit of detection was 15.49 pmol/L and the limit of quantitation was 140.78 pmol/L. Biological validation was achieved by comparison of samples previously run by radioimmunoassay and measurement of the marmoset insulin response to glucose via an oral glucose tolerance test (OGTT). The physiological range of marmoset insulin was shown to be 84.5 to 1222 pmol/L. In summary, this paper presents a simple, reproducible method to measure marmoset insulin in serum using LC-MS/MS.
Sujet(s)
Callithrix/physiologie , Chromatographie en phase liquide/méthodes , Insuline/sang , Spectrométrie de masse en tandem/méthodes , Animaux , Modèles animaux de maladie humaine , Femelle , Limite de détection , Modèles linéaires , Mâle , Syndrome métabolique X , Reproductibilité des résultatsRÉSUMÉ
Depression and anxiety are some of the most prevalent and debilitating mental health conditions in humans. They can present on their own or as co-morbidities with other disorders. Like humans, non-human primates (NHPs) can develop depression- and anxiety-like signs. Here, we first define human depression and anxiety, examine equivalent species-specific behaviors in NHPs, and consider models and current methods to identify and evaluate these behaviors. We also discuss knowledge gaps, as well as the importance of evaluating the co-occurrence of depression- and anxiety-like behaviors in animal models of human disease. Lastly, we consider ethical challenges in depression and anxiety research on NHPs in order to ultimately advance the understanding and the personalized treatment of these disorders.
RÉSUMÉ
Nonhuman primates (NHPs) are a critical component of translational/preclinical biomedical research due to the strong similarities between NHP and human physiology and disease pathology. In some cases, NHPs represent the most appropriate, or even the only, animal model for complex metabolic, neurological, and infectious diseases. The increased demand for and limited availability of these valuable research subjects requires that rigor and reproducibility be a prime consideration to ensure the maximal utility of this scarce resource. Here, we discuss a number of approaches that collectively can contribute to enhanced rigor and reproducibility in NHP research.
Sujet(s)
Recherche biomédicale , Primates , Animaux , Modèles animaux de maladie humaine , Reproductibilité des résultatsRÉSUMÉ
Aging leads to profound changes in glucose homeostasis, weight, and adiposity, which are considered good predictors of health and survival in humans. Direct evidence that these age-associated metabolic alterations are recapitulated in animal models is lacking, impeding progress to develop and test interventions that delay the onset of metabolic dysfunction and promote healthy aging and longevity. We compared longitudinal trajectories, rates of change, and mortality risks of fasting blood glucose, body weight, and fat mass in mice, nonhuman primates, and humans throughout their lifespans and found similar trajectories of body weight and fat in the three species. In contrast, fasting blood glucose decreased late in life in mice but increased over the lifespan of nonhuman primates and humans. Higher glucose was associated with lower mortality in mice but higher mortality in nonhuman primates and humans, providing a cautionary tale for translating age-associated metabolic changes from mice to humans.
Sujet(s)
Glycémie , Jeûne , Adiposité , Animaux , Glycémie/métabolisme , Longévité , Souris , Obésité/métabolismeRÉSUMÉ
Age is a major risk factor for late-onset Alzheimer's disease (AD) but seldom features in laboratory models of the disease. Furthermore, heterogeneity in size and density of AD plaques observed in individuals are not recapitulated in transgenic mouse models, presenting an incomplete picture. We show that the amyloid plaque microenvironment is not equivalent between rodent and primate species, and that differences in the impact of AD pathology on local metabolism and inflammation might explain established differences in neurodegeneration and functional decline. Using brain tissue from transgenic APP/PSEN1 mice, rhesus monkeys with age-related amyloid plaques, and human subjects with confirmed AD, we report altered energetics in the plaque microenvironment. Metabolic features included changes in mitochondrial distribution and enzymatic activity, and changes in redox cofactors NAD(P)H that were shared among species. A greater burden of lipofuscin was detected in the brains from monkeys and humans of advanced age compared to transgenic mice. Local inflammatory signatures indexed by astrogliosis and microglial activation were detected in each species; however, the inflamed zone was considerably larger for monkeys and humans. These data demonstrate the advantage of nonhuman primates in modeling the plaque microenvironment, and provide a new framework to investigate how AD pathology might contribute to functional loss.
Sujet(s)
Maladie d'Alzheimer , Animaux , Modèles animaux de maladie humaine , Macaca mulattaRÉSUMÉ
BACKGROUND: A survey was developed to characterize disease incidence, common pathology lesions, environmental characteristics, and nutrition programs within captive research marmoset colonies. METHODS: Seventeen research facilities completed the electronic survey. RESULTS: Nutritional management programs varied amongst research institutions housing marmosets; eight primary base diets were reported. The most common clinical syndromes reported were gastrointestinal disease (i.e. inflammatory bowel disease like disease, chronic lymphocytic enteritis, chronic malabsorption, chronic diarrhea), metabolic bone disease or fracture, infectious diarrhea, and oral disease (tooth root abscesses, gingivitis, tooth root resorption). The five most common pathology morphologic diagnoses were colitis, nephropathy/nephritis, enteritis, chronic lymphoplasmacytic enteritis, and cholecystitis. Obesity was more common (average 20% of a reporting institution's population) than thin body condition (average 5%). CONCLUSIONS: Through review of current practices, we aim to inspire development of evidence-based practices to standardize husbandry and nutrition practices for marmoset research colonies.