Aged Monkeys Research Articles

Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates

Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.

Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition.

Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.

Evolutionarily conserved neural responses to affective touch in monkeys transcend consciousness and change with age

Affective touch-a slow, gentle, and pleasant form of touch-activates a different neural network than which is activated during discriminative touch in humans. Affective touch perception is enabled by specialized low-threshold mechanoreceptors in the skin with unmyelinated fibers called C tactile (CT) afferents. These CT afferents are conserved across mammalian species, including macaque monkeys. However, it is unknown whether the neural representation of affective touch is the same across species and whether affective touch's capacity to activate the hubs of the brain that compute socioaffective information requires conscious perception. Here, we used functional MRI to assess the preferential activation of neural hubs by slow (affective) vs. fast (discriminative) touch in anesthetized rhesus monkeys (Macaca mulatta). The insula, anterior cingulate cortex (ACC), amygdala, and secondary somatosensory cortex were all significantly more active during slow touch relative to fast touch, suggesting homologous activation of the interoceptive-allostatic network across primate species during affective touch. Further, we found that neural responses to affective vs. discriminative touch in the insula and ACC (the primary cortical hubs for interoceptive processing) changed significantly with age. Insula and ACC in younger animals differentiated between slow and fast touch, while activity was comparable between conditions for aged monkeys (equivalent to >70 y in humans). These results, together with prior studies establishing conserved peripheral nervous system mechanisms of affective touch transduction, suggest that neural responses to affective touch are evolutionarily conserved in monkeys, significantly impacted in old age, and do not necessitate conscious experience of touch.

Management of cognitive symptoms in schizophrenia.

IntroductionCognitive impairment is the frequent symptom occurring in nonelderly patients with schizophrenia or other neurodegenerative disorders. Cognitive dysfunction in patients with schizophrenia was described by Kraepelin more than a century ago. Increased awareness and advancements in the area of neuropsychological assessment and neuroimaging techniques have now rendered cognitive impairment an important focus of theories on the etiology and treatment of schizophrenia. Cognitive enhancement still remains a clinically unresolved challenge. Till date, there is no effective treatment available for enhancing cognitive function in patients with schizophreniaObjectivesThis e-poster aimed to summarize evidence regarding clinical data on the nonpharmacologic and pharmacologic management of cognitive symptoms of schizophrenia, also known as cognitive impairment associated with schizophrenia (CIAS), and highlight the selection of appropriate treatment options.MethodsA bibliopgraphical review was performed using PubMed platform. All relevant articles were found using the keywords: schizophrenia, cognitive symptoms, menagement.ResultsMany different drug targets and strategies for drug development have been employed for enhancement of cognition in schizophrenia. Receptor targets have been identified on the basis of pharmacologic challenges that mimic schizophrenia (e.g., dopamine agonists and NMDA receptor antagonists), receptor abnormalities found on postmortem analysis of schizophrenia brain, and genetic linkage studies. Treatment with a D1 agonist was shown to “sensitize” D1 receptors and improve memory in both aged and antipsychotic-treated monkeys. Clinical trials of D1 agonists in schizophrenia have been delayed due to poor tolerability related to orthostatic hypotension and nausea. The glycine-site agonists, glycine, D-serine, and D-alanine, produced improvement in negative symptoms in small trials and some improvement in measures of cognition, although formal cognitive testing was not performed.ConclusionsAlthough the evidence supporting cognitive remediation has not yet achieved the level necessary to merit inclusion in evidence-based treatment guidelines, this approach, combined with other psychosocial interventions, is promising. Several pharmacologic approaches are currently under study to facilitate neuroplasticity.Disclosure of InterestNone Declared

Bearded capuchin monkeys as a model for Alzheimer's disease.

The absence of a natural animal model is one of the main challenges in Alzheimer's disease research. Despite the challenges of using nonhuman primates in studies, these animals can bridge mouse models and humans, as nonhuman primates are phylogenetically closer to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed one capuchin brain using structural 7T MRI and performed a neuropathological evaluation of three animals. Alzheimer-type pathology was found in the two of the capuchins. Widespread β-amyloid pathology was observed, mainly in focal deposits with variable morphology and a high density of mature plaques. Notably, plaque-associated dystrophic neurites associated with disruption of axonal transport and early cytoskeletal alteration were frequently found. Unlike in other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of β-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. These findings indicate that aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimer's disease.

See no evil: Attentional bias toward threat is diminished in aged monkeys.

Prior evidence demonstrates that relative to younger adults, older human adults exhibit attentional biases toward positive and/or away from negative socioaffective stimuli (i.e., the age-related positivity effect). Whether or not the effect is phylogenetically conserved is currently unknown and its biopsychosocial origins are debated. To address this gap, we evaluated how visual processing of socioaffective stimuli differs in aged, compared to middle-aged, rhesus monkeys (Macaca mulatta) using eye tracking in two experimental designs that are directly comparable to those historically used for evaluating attentional biases in humans. Results of our study demonstrate that while younger rhesus possesses robust attentional biases toward threatening pictures of conspecifics' faces, aged animals evidence no such bias. Critically, these biases emerged only when threatening faces were paired with neutral and not ostensibly "positive" faces, suggesting social context modifies the effect. Results of our study suggest that the evolutionarily shared mechanisms drive age-related decline in visual biases toward negative stimuli in aging across primate species. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

SHIV-C109p5 NHP induces rapid disease progression in elderly macaques with extensive GI viral replication.

CCR5-tropic simian/human immunodeficiency viruses (SHIV) with clade C transmitted/founder envelopes represent a critical tool for the investigation of HIV experimental vaccines and microbicides in nonhuman primates, although many such isolates lead to spontaneous viral control post infection. Here, we generated a high-titer stock of pathogenic SHIV-C109p5 by serial passage in two rhesus macaques (RM) and tested its virulence in aged monkeys. The co-receptor usage was confirmed before infecting five geriatric rhesus macaques (four female and one male). Plasma viral loads were monitored by reverse transcriptase-quantitative PCR (RT-qPCR), cytokines by multiplex analysis, and biomarkers of gastrointestinal damage by enzyme-linked immunosorbent assay. Antibodies and cell-mediated responses were also measured. Viral dissemination into tissues was determined by RNAscope. Intravenous SHIV-C109p5 infection of aged RMs leads to high plasma viremia and rapid disease progression; rapid decrease in CD4+ T cells, CD4+CD8+ T cells, and plasmacytoid dendritic cells; and wasting necessitating euthanasia between 3 and 12 weeks post infection. Virus-specific cellular immune responses were detected only in the two monkeys that survived 4 weeks post infection. These were Gag-specific TNFα+CD8+, MIP1β+CD4+, Env-specific IFN-γ+CD4+, and CD107a+ T cell responses. Four out of five monkeys had elevated intestinal fatty acid binding protein levels at the viral peak, while regenerating islet-derived protein 3α showed marked increases at later time points in the three animals surviving the longest, suggesting gut antimicrobial peptide production in response to microbial translocation post infection. Plasma levels of monocyte chemoattractant protein-1, interleukin-15, and interleukin-12/23 were also elevated. Viral replication in gut and secondary lymphoid tissues was extensive.IMPORTANCESimian/human immunodeficiency viruses (SHIV) are important reagents to study prevention of virus acquisition in nonhuman primate models of HIV infection, especially those representing transmitted/founder (T/F) viruses. However, many R5-tropic SHIV have limited fitness in vivo leading to many monkeys spontaneously controlling the virus post acute infection. Here, we report the generation of a pathogenic SHIV clade C T/F stock by in vivo passage leading to sustained viral load set points, a necessity to study pathogenicity. Unexpectedly, administration of this SHIV to elderly rhesus macaques led to extensive viral replication and fast disease progression, despite maintenance of a strict R5 tropism. Such age-dependent rapid disease progression had previously been reported for simian immunodeficiency virus but not for R5-tropic SHIV infections.

Insights into Novel Therapies and the Pathogenesis of Alzheimer's disease, and the Possible Role of COVID-19

The Wisniewski laboratory has helped develop novel biomarkers and therapeutic approaches to AD, particular immunotherapeutic approaches that affect both the adaptive and innate immune systems. We have developed a means to stimulate innate immunity to ameliorate AD pathology, which we have tested in aged squirrel monkeys, and now are conducting a phase I clinical trial. We have also developed both active and passive immunization that specifically targets the dominant β-sheet secondary structure of multiple toxic oligomers concurrently (including both Aβ and tau oligomers). Recently we have also documented the neurological manifestations of SARS-CoV-2 infection (in particular cognitive dysfunction) and associated biomarkers of neurodegeneration and neuroinflammation. We have also developed an unbiased proteomic methodology that produces robust data utilizing archival formalin, fixed paraffin embedded human tissue, using this method to perform the most extensive proteomic analysis of amyloid plaques and the phosphorylated tau interaction, as well as to characterize the amyloid proteome of distinct subtypes of AD including rapidly progressive AD and AD in Down syndrome. These studies have helped enhance the understanding of the pathogenesis of AD, and also with the development of novel therapies.

Correlation analysis of positron emission tomography/computed tomography-magnetic resonance imaging of cannabinoid type 1 receptor in the lumbar spine and brain of aged osteoporosis female cynomolgus monkeys.

Although cannabinoid receptor 1 (CB1R) antagonists can inhibit bone loss in osteoporosis mouse models, different strains of mice show different bone mass phenotypes after knock out the CB1R gene. The relationship between CB1R and bone metabolism is complex, and its regulatory role in bone metabolism and as a therapeutic target for osteoporosis requires further investigation. Based on lumbar spine volumetric bone mineral density (vBMD) data of healthy female cynomolgus monkeys aged 1-25 years, naturally aged postmenopausal female osteoporotic monkeys and normal young monkeys were screened by detecting lumbar vertebrae vBMD and estradiol levels in this study. Positron emission tomography-computed tomography (PET/CT) and magnetic resonance imaging (MRI) scans were performed on the lumbar spine and brain of the two groups of monkeys using the probe [11C]OMAR, which specifically targets CB1R, and the difference in the CB1R expression of osteoporotic monkeys was evaluated. The vBMD values of two standard deviations (SDs) below the peak bone value (428.1±53.8 g/cm3) were set as the reference standard for osteoporosis vBMD. Of the 49 healthy female cynomolgus monkeys, 4 postmenopausal older osteoporotic monkeys (18-26 years) and 5 young control monkeys (6-7 years) were selected, and the mean vBMD of the lumbar spine of the two groups was 295.07±19.11 and 419.72±16.14 g/cm3, respectively (P<0.0001). Radioactive uptake in the lumbar spine was linearly and negatively correlated with vBMD (r=-0.7977; P=0.01). Dynamic PET/MR imaging of the brains showed that CB1R was upregulated in the osteoporosis group, and there was a negative linear correlation between the vBMD and area under the time-radioactivity curve (AUC) of the thalamus (r=-0.8506; P=0.0153) and prefrontal cortex (r=-0.8306; P=0.0207). In this study, PET/CT-MRI molecular imaging technology revealed that CB1R was upregulated in the lumbar spine and brain of the osteoporosis monkeys and that CB1R may be regulated by the brain-bone axis. CB1R antagonist may be a potential drug for the treatment of osteoporosis.

CHIT1-positive microglia drive motor neuron ageing in the primate spinal cord.

Ageing is a critical factor in spinal-cord-associated disorders1, yet the ageing-specific mechanisms underlying this relationship remain poorly understood. Here, to address this knowledge gap, we combined single-nucleus RNA-sequencing analysis with behavioural and neurophysiological analysis in non-human primates (NHPs). We identified motor neuron senescence and neuroinflammation with microglial hyperactivation as intertwined hallmarks of spinal cord ageing. As an underlying mechanism, we identified a neurotoxic microglial state demarcated by elevated expression of CHIT1 (a secreted mammalian chitinase) specific to the aged spinal cords in NHP and human biopsies. In the aged spinal cord, CHIT1-positive microglia preferentially localize around motor neurons, and they have the ability to trigger senescence, partly by activating SMAD signalling. We further validated the driving role of secreted CHIT1 on MN senescence using multimodal experiments both in vivo, using the NHP spinal cord as a model, and in vitro, using a sophisticated system modelling the human motor-neuron-microenvironment interplay. Moreover, we demonstrated that ascorbic acid, a geroprotective compound, counteracted the pro-senescent effect of CHIT1 and mitigated motor neuron senescence in aged monkeys. Our findings provide the single-cell resolution cellular and molecular landscape of the aged primate spinal cord and identify a new biomarker and intervention target for spinal cord degeneration.

Cardiac psychophysiological tuning to socioaffective content is disrupted in aged rhesus monkeys (Macaca mulatta).

Aging ushers in numerous disruptions to autonomic nervous system (ANS) function. Although the effects of aging on ANS function at rest are well characterized, there is surprising variation in reports of age-related differences in ANS reactivity to psychosocial stressors, with some reports of decreases and other reports of increases in reactivity with age. The sources of variation in age-related differences are largely unknown. Nonhuman primate models of socioaffective aging may help to uncover sources of this variation as nonhuman primates share key features of human ANS structure and function and researchers have precise control over the environments in which they age. In this report, we assess how response patterns to dynamic socioaffective stimuli in the parasympathetic and sympathetic branches of rhesus monkeys (Macaca mulatta) ANS differ in aged compared to middle-aged monkeys. We find that respiratory sinus arrhythmia, a cardiac indicator of activity in the parasympathetic branch of the ANS, exhibits age-related disruptions in responding while monkeys view videos of conspecifics. This suggests that there are evolutionarily conserved mechanisms responsible for the patterns of affective aging observed in humans and that aged rhesus monkeys are a robust translational model for human affective aging.

Label-free autofluorescence and hyperspectral imaging of cerebral amyloid-β lesions in aged squirrel monkeys.

The observation of amyloid-β (Aβ) lesions using autofluorescence in transgenic mice and human Alzheimer disease patients has been reported frequently. However, no reports verify the autofluorescence of spontaneous Aβ amyloidosis in animals, to our knowledge. We validated the autofluorescence of Aβ lesions in spontaneous squirrel monkey cases under label-free conditions; lesions had intense blue-white autofluorescence in fluorescence microscopy using excitation light at 400-440 nm. Thioflavin S staining and immunohistochemistry of the same specimens revealed that this blue-white autofluorescence was derived from Aβ lesions. Hyperspectral analysis of these lesions revealed a characteristic spectrum with bimodal peaks at 440 and 460 nm, as reported for Aβ lesions in mice. Principal component analysis using hyperspectral data specifically separated the Aβ lesions from other autofluorescent substances, such as lipofuscin. A non-labeled and mechanistic detection of Aβ lesions by hyperspectral imaging could provide valuable insights for developing early diagnostic techniques.

Cognitive Aging and the Primate Basal Forebrain Revisited: Disproportionate GABAergic Vulnerability Revealed.

Basal forebrain (BF) projections to the hippocampus and cortex are anatomically positioned to influence a broad range of cognitive capacities that are known to decline in normal aging, including executive function and memory. Although a long history of research on neurocognitive aging has focused on the role of the cholinergic basal forebrain system, intermingled GABAergic cells are numerically as prominent and well positioned to regulate the activity of their cortical projection targets, including the hippocampus and prefrontal cortex. The effects of aging on noncholinergic BF neurons in primates, however, are largely unknown. In this study, we conducted quantitative morphometric analyses in brains from young adult (6 females, 2 males) and aged (11 females, 5 males) rhesus monkeys (Macaca mulatta) that displayed significant impairment on standard tests that require the prefrontal cortex and hippocampus. Cholinergic (ChAT+) and GABAergic (GAD67+) neurons were quantified through the full rostrocaudal extent of the BF. Total BF immunopositive neuron number (ChAT+ plus GAD67+) was significantly lower in aged monkeys compared with young, largely because of fewer GAD67+ cells. Additionally, GAD67+ neuron volume was greater selectively in aged monkeys without cognitive impairment compared with young monkeys. These findings indicate that the GABAergic component of the primate BF is disproportionally vulnerable to aging, implying a loss of inhibitory drive to cortical circuitry. Moreover, adaptive reorganization of the GABAergic circuitry may contribute to successful neurocognitive outcomes.SIGNIFICANCE STATEMENT A long history of research has confirmed the role of the basal forebrain in cognitive aging. The majority of that work has focused on BF cholinergic neurons that innervate the cortical mantle. Codistributed BF GABAergic populations are also well positioned to influence cognitive function, yet little is known about this prominent neuronal population in the aged brain. In this unprecedented quantitative comparison of both cholinergic and GABAergic BF neurons in young and aged rhesus macaques, we found that neuron number is significantly reduced in the aged BF compared with young, and that this reduction is disproportionately because of a loss of GABAergic neurons. Together, our findings encourage a new perspective on the functional organization of the primate BF in neurocognitive aging.

SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B.

Aging is a major risk factor contributing to pathophysiological changes in the heart, yet its intrinsic mechanisms have been largely unexplored in primates. In this study, we investigated the hypertrophic and senescence phenotypes in the hearts of aged cynomolgus monkeys as well as the transcriptomic and proteomic landscapes of young and aged primate hearts. SIRT2 was identified as a key protein decreased in aged monkey hearts, and engineered SIRT2 deficiency in human pluripotent stem cell-derived cardiomyocytes recapitulated key senescence features of primate heart aging. Further investigations revealed that loss of SIRT2 in human cardiomyocytes led to the hyperacetylation of STAT3, which transcriptionally activated CDKN2B and, in turn, triggered cardiomyocyte degeneration. Intra-myocardial injection of lentiviruses expressing SIRT2 ameliorated age-related cardiac dysfunction in mice. Taken together, our study provides valuable resources for decoding primate cardiac aging and identifies the SIRT2-STAT3-CDKN2B regulatory axis as a potential therapeutic target against human cardiac aging and aging-related cardiovascular diseases.

Chronic GCPII (glutamate-carboxypeptidase-II) inhibition reduces pT217Tau levels in the entorhinal and dorsolateral prefrontal cortices of aged macaques.

Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1-42 (Aβ1-42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post-synaptic, on spines, where they regulate cAMP-calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally-occurring tau pathology. Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)),Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)). Aged macaques that received 2-MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2-MPPA- and vehicle-treated monkeys showed cognitive improvement; 2-MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2-MPPA administration, confirmed in dlPFC samples. These data provide proof-of-concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Inflammation is a key driver of sporadic Alzheimer's disease.GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium.Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys.GCPII inhibition is a novel strategy to help prevent tau pathology at early stages.

Mesenchymal-derived extracellular vesicles enhance microglia-mediated synapse remodeling after cortical injury in aging Rhesus monkeys

Understanding the microglial neuro-immune interactions in the primate brain is vital to developing therapeutics for cortical injury, such as stroke or traumatic brain injury. Our previous work showed that mesenchymal-derived extracellular vesicles (MSC-EVs) enhanced motor recovery in aged rhesus monkeys following injury of primary motor cortex (M1), by promoting homeostatic ramified microglia, reducing injury-related neuronal hyperexcitability, and enhancing synaptic plasticity in perilesional cortices. A focal lesion was induced via surgical ablation of pial blood vessels over lying the cortical hand representation of M1 of aged female rhesus monkeys, that received intravenous infusions of either vehicle (veh) or EVs 24 h and again 14 days post-injury. The current study used this same cohort to address how these injury- and recovery-associated changes relate to structural and molecular interactions between microglia and neuronal synapses. Using multi-labeling immunohistochemistry, high-resolution microscopy, and gene expression analysis, we quantified co-expression of synaptic markers (VGLUTs, GLURs, VGAT, GABARs), microglia markers (Iba1, P2RY12), and C1q, a complement pathway protein for microglia-mediated synapse phagocytosis, in perilesional M1 and premotor cortices (PMC). We compared this lesion cohort to age-matched non-lesion controls (ctr). Our findings revealed a lesion-related loss of excitatory synapses in perilesional areas, which was ameliorated by EV treatment. Further, we found region-dependent effects of EVs on microglia and C1q expression. In perilesional M1, EV treatment and enhanced functional recovery were associated with increased expression of C1q + hypertrophic microglia, which are thought to have a role in debris-clearance and anti-inflammatory functions. In PMC, EV treatment was associated with decreased C1q + synaptic tagging and microglia–spine contacts. Our results suggest that EV treatment may enhance synaptic plasticity via clearance of acute damage in perilesional M1, and thereby preventing chronic inflammation and excessive synaptic loss in PMC. These mechanisms may act to preserve synaptic cortical motor networks and a balanced normative M1/PMC synaptic function to support functional recovery after injury.

Transcriptomic changes in the hypothalamus of rhesus monkeys with bone marrow mesenchymal stem cells treatment

Background: It is acknowledged that the hypothalamus plays an important role in the regulation of aging, and bone marrow mesenchymal stem cells (BMSCs) possess an anti-aging effect, this study was therefore designed to investigate transcriptomic changes in the hypothalamus of aged rhesus monkeys with BMSCs-treatment to explore the underlying molecular mechanism for the anti-aging effect of BMSCs. Methods: Transcriptome profiling sequencing was conducted on the juvenile rhesus macaques (YN), adult rhesus macaques (QN), aged rhesus macaques (LN) and BMSCs-treated aged rhesus macaques (ZL). Then, differentially expressed genes (DEG) analysis was performed between YN and QN, QN and LN, LN and ZL, respectively. After the intersection of DEGs from these three pairs of comparisons, screened intersecting genes were subject to GO (Gene Ontology) enrichment analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and PPI (protein-protein interaction) analysis to explore their interactions and underlying mechanism of BMSCs for retarding aging. Lastly, according to the results of PPI and the most enriched GO term, we further integrated and screened genes, which were regarded as aging-related genes in the hypothalamus. Results: According to obtained transcriptome profiling data, 671 differentially expressed genes were screened between QN and YN, 1315 genes between LN and QN, and 1345 genes between ZL and LN. After intersecting, 53 genes were screened out. GO analysis showed that most genes were mainly enriched in intercellular adhesion, sphingosinol biosynthesis, ceramide biosynthesis in BP, while in the cell membrane group and Golgi membrane in CC. PPI suggested that SPTLC2, ASAH2, FA2H and other genes had higher core degrees, indicating these hub genes may be involved in the process of aging by lipid metabolism. After the final screening, a total of 28 genes with significant differences were screened out, among which GPR68, LOC706331, STRA6 and PDE7B were up-regulated in QN and ZL compared with YN and LN respectively, while down-regulated in LN compared with QN. The other 24 genes were down-regulated in QN and ZL compared with YN and LN respectively, while up-regulated in LN compared with QN. Conclusion: A total of 28 genes were recognized as aging-related genes in the hypothalamus, and BMSCs treatment for retarding aging may be involved in these gene targets.

Neuropsychology of cognitive aging in rhesus monkeys

Aged rhesus monkeys, like aged humans, show declines in cognitive function. We present cognitive test data from a large sample of male and female rhesus monkeys, 34 young (aged 3.5–13.6 years) and 71 aged (aged 19.9–32.5 years at the start of cognitive testing). Monkeys were tested on spatiotemporal working memory (delayed response), visual recognition memory (delayed nonmatching to sample), and stimulus-reward association learning (object discrimination), tasks with an extensive evidence base in nonhuman primate neuropsychology. On average, aged monkeys performed worse than young on all 3 tasks. Acquisition of delayed response and delayed nonmatching to sample was more variable in aged monkeys than in young. Performance scores on delayed nonmatching to sample and object discrimination were associated with each other, but neither was associated with performance on delayed response. Sex and chronological age were not reliable predictors of individual differences in cognitive outcome among the aged monkeys. These data establish population norms for multiple cognitive tests in young and aged rhesus monkeys in the largest sample reported to date. They also illustrate independence of cognitive aging in task domains dependent on the prefrontal cortex and medial temporal lobe.

Alignment of human aquaporin 4 and ß-amyloid proteins may indicate involvement of ß-amyloid in brain water homeostasis and prevention of brain edema.

Alignment of human aquaporin 4 and ß-amyloid proteins may indicate involvement of ß-amyloid in brain water homeostasis and prevention of brain edema.

Comparison of differential metabolites in brain tissue of aged marmosets and serum of elderly patients after prolonged anesthesia.

To compare the differential metabolites in the brain tissue of aged marmosets after long-term anesthesia (≥ 6 h) and the serum of elderly patients by metabolomics methods. Six aged marmosets (≥ 8 years old) were divided into two groups: anesthesia and control. The aged monkeys in the anesthesia group were induced with 6-8% sevoflurane and 100% oxygen (2 l/min) for 1-2 min and maintained with 1.5-2.5% sevoflurane and 100% oxygen (2 l/min) for 6 h. In the control group (n = 3), anesthesia was only induced under the same conditions for 1-2 min. The prefrontal cortex tissues of the two groups of aged marmosets were collected for metabolomics detection. Twenty-nine elderly patients (≥ 65 years old) who had undergone surgical anesthesia for more than 6 h were enrolled. Serum samples were collected before and on the first day after surgery for metabolomics analysis. Differential metabolites were compared between human serum and marmoset brain tissue. The changes in lactate and xanthurenic acid in the serum of elderly patients were consistent with those in the brain tissue of aged marmoset monkeys, that is, lactate was up-regulated and xanthurenic acid was down-regulated. However, serum levels of 5-methylterahydrofolic acid and leucine were down-regulated in elderly patients after anesthesia. In contrast, 5-methylterahydrofolic acid and leucine levels were up-regulated in the prefrontal cortex of aged marmosets compared with control marmosets. Furthermore, glycolysis/gluconeogenesis and pentose phosphate pathway were both significantly enriched in the prefrontal cortex of aged marmosets and serum of elderly patients after surgery. The changes of serum metabolites in elderly patients are not exactly the same as the metabolic changes of brain tissues in aged marmosets. The metabolic changes in serum lactate and xanthurenic acid levels can reflect brain tissue metabolism. The enrichment pathways of differential metabolites in the serum of elderly patients and the brain tissue of aged marmosets were partially the same.