RESUMO
Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1+/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease.
Assuntos
Cognição/fisiologia , Suturas Cranianas/fisiopatologia , Craniossinostoses/fisiopatologia , Regeneração/fisiologia , Crânio/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Craniossinostoses/genética , Dura-Máter/patologia , Dura-Máter/fisiopatologia , Gelatina/farmacologia , Perfilação da Expressão Gênica , Força da Mão , Pressão Intracraniana/efeitos dos fármacos , Pressão Intracraniana/fisiologia , Locomoção/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Metacrilatos/farmacologia , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Crânio/patologia , Proteína 1 Relacionada a Twist/metabolismo , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
γ-Secretase proteases have been associated with pathology in Alzheimer disease (AD), but we are just beginning to understand their basic mechanisms and physiological roles. A negative drug trial with a broad spectrum γ-secretase inhibitor in AD patients has severely dampened enthusiasm for the potential of pursuing γ-secretase research therapeutically. This pessimism is unwarranted: analysis of available information presented here demonstrates significant confounds for interpreting the outcome of the trial and argues that the major lessons pertain to broad knowledge gaps that are imperative to fill.
Assuntos
Alanina/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Azepinas/efeitos adversos , Ensaios Clínicos como Assunto , Alanina/efeitos adversos , Alanina/farmacocinética , Alanina/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Azepinas/farmacocinética , Azepinas/uso terapêutico , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , HumanosRESUMO
Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population1. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments. Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.
Assuntos
Envelhecimento , Cognição , Disfunção Cognitiva , Doenças Neuroinflamatórias , Nootrópicos , Fator Plaquetário 4 , Animais , Masculino , Camundongos , Envelhecimento/sangue , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/complicações , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/prevenção & controle , Fator Plaquetário 4/sangue , Fator Plaquetário 4/metabolismo , Fator Plaquetário 4/farmacologia , Fator Plaquetário 4/uso terapêutico , Nootrópicos/sangue , Nootrópicos/metabolismo , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Plasma/química , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/prevenção & controle , Transcrição Gênica/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacosRESUMO
Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer's disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1ß2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brain's endogenous γ-oscillations through enhancing the function of PV+INs.
Assuntos
Doença de Alzheimer , Cognição , Modelos Animais de Doenças , Ritmo Gama , Animais , Doença de Alzheimer/tratamento farmacológico , Camundongos , Cognição/efeitos dos fármacos , Ritmo Gama/efeitos dos fármacos , Memória/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Camundongos Transgênicos , Humanos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Alanina/análogos & derivados , AzepinasRESUMO
A balanced excitation-inhibition ratio (E/I ratio) is critical for healthy brain function. Normative development of cortex-wide E/I ratio remains unknown. Here, we noninvasively estimate a putative marker of whole-cortex E/I ratio by fitting a large-scale biophysically plausible circuit model to resting-state functional MRI (fMRI) data. We first confirm that our model generates realistic brain dynamics in the Human Connectome Project. Next, we show that the estimated E/I ratio marker is sensitive to the gamma-aminobutyric acid (GABA) agonist benzodiazepine alprazolam during fMRI. Alprazolam-induced E/I changes are spatially consistent with positron emission tomography measurement of benzodiazepine receptor density. We then investigate the relationship between the E/I ratio marker and neurodevelopment. We find that the E/I ratio marker declines heterogeneously across the cerebral cortex during youth, with the greatest reduction occurring in sensorimotor systems relative to association systems. Importantly, among children with the same chronological age, a lower E/I ratio marker (especially in the association cortex) is linked to better cognitive performance. This result is replicated across North American (8.2 to 23.0 y old) and Asian (7.2 to 7.9 y old) cohorts, suggesting that a more mature E/I ratio indexes improved cognition during normative development. Overall, our findings open the door to studying how disrupted E/I trajectories may lead to cognitive dysfunction in psychopathology that emerges during youth.
Assuntos
Córtex Cerebral , Cognição , Imageamento por Ressonância Magnética , Humanos , Cognição/fisiologia , Cognição/efeitos dos fármacos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Masculino , Imageamento por Ressonância Magnética/métodos , Feminino , Adolescente , Criança , Conectoma/métodos , Alprazolam/farmacologia , Receptores de GABA-A/metabolismo , Adulto JovemRESUMO
Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for treating motor symptoms, these interventions can lead to further worsening of speech. The interplay between dopaminergic medication, STN circuitry, and their downstream effects on speech in PD is not yet fully understood. Here, we investigate the effect of dopaminergic medication on STN circuitry and probe its association with speech and cognitive functions in PD patients. We found that changes in intrinsic functional connectivity of the STN were associated with alterations in speech functions in PD. Interestingly, this relationship was characterized by altered functional connectivity of the dorsolateral and ventromedial subdivisions of the STN with the language network. Crucially, medication-induced changes in functional connectivity between the STN's dorsolateral subdivision and key regions in the language network, including the left inferior frontal cortex and the left superior temporal gyrus, correlated with alterations on a standardized neuropsychological test requiring oral responses. This relation was not observed in the written version of the same test. Furthermore, changes in functional connectivity between STN and language regions predicted the medication's downstream effects on speech-related cognitive performance. These findings reveal a previously unidentified brain mechanism through which dopaminergic medication influences speech function in PD. Our study sheds light into the subcortical-cortical circuit mechanisms underlying impaired speech control in PD. The insights gained here could inform treatment strategies aimed at mitigating speech deficits in PD and enhancing the quality of life for affected individuals.
Assuntos
Idioma , Doença de Parkinson , Fala , Núcleo Subtalâmico , Humanos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Núcleo Subtalâmico/fisiopatologia , Núcleo Subtalâmico/efeitos dos fármacos , Masculino , Fala/fisiologia , Fala/efeitos dos fármacos , Feminino , Pessoa de Meia-Idade , Idoso , Imageamento por Ressonância Magnética , Dopamina/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiopatologia , Cognição/efeitos dos fármacos , Dopaminérgicos/farmacologia , Dopaminérgicos/uso terapêuticoRESUMO
BACKGROUND: The accumulation of soluble and insoluble aggregated amyloid-beta (Aß) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aß soluble protofibrils, is being tested in persons with early Alzheimer's disease. METHODS: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment). RESULTS: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%. CONCLUSIONS: Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).
Assuntos
Doença de Alzheimer , Anticorpos Monoclonais Humanizados , Nootrópicos , Humanos , Atividades Cotidianas , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Cognição/efeitos dos fármacos , Método Duplo-Cego , Nootrópicos/efeitos adversos , Nootrópicos/farmacologia , Nootrópicos/uso terapêuticoRESUMO
Acute cannabis intoxication may induce neurocognitive impairment and is a possible cause of human error, injury and psychological distress. One of the major concerns raised about increasing cannabis legalization and the therapeutic use of cannabis is that it will increase cannabis-related harm. However, the impairing effect of cannabis during intoxication varies among individuals and may not occur in all users. There is evidence that the neurocognitive response to acute cannabis exposure is driven by changes in the activity of the mesocorticolimbic and salience networks, can be exacerbated or mitigated by biological and pharmacological factors, varies with product formulations and frequency of use and can differ between recreational and therapeutic use. It is argued that these determinants of the cannabis-induced neurocognitive state should be taken into account when defining and evaluating levels of cannabis impairment in the legal arena, when prescribing cannabis in therapeutic settings and when informing society about the safe and responsible use of cannabis.
Assuntos
Canabinoides/farmacologia , Cannabis , Cognição/efeitos dos fármacos , Envelhecimento , Atenção/efeitos dos fármacos , Variação Biológica Individual , Biotransformação/genética , Encéfalo/efeitos dos fármacos , Canabinoides/administração & dosagem , Canabinoides/farmacocinética , Estado de Consciência/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Dronabinol/farmacocinética , Dronabinol/farmacologia , Tolerância a Medicamentos , Feminino , Humanos , Aprendizagem/efeitos dos fármacos , Masculino , Fumar Maconha , Rede Nervosa/efeitos dos fármacos , Neurotransmissores/farmacologia , Personalidade , Desempenho Psicomotor/efeitos dos fármacos , Psicotrópicos/administração & dosagem , Psicotrópicos/farmacologia , Caracteres Sexuais , FumaçaRESUMO
BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-ß peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. CONCLUSIONS: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.
Assuntos
Aminobutiratos , Antagonistas de Receptores de Angiotensina , Compostos de Bifenilo , Cognição , Combinação de Medicamentos , Insuficiência Cardíaca , Volume Sistólico , Tetrazóis , Valsartana , Humanos , Compostos de Bifenilo/uso terapêutico , Valsartana/uso terapêutico , Valsartana/efeitos adversos , Aminobutiratos/uso terapêutico , Aminobutiratos/efeitos adversos , Masculino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Feminino , Idoso , Cognição/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/efeitos adversos , Pessoa de Meia-Idade , Tetrazóis/uso terapêutico , Tetrazóis/efeitos adversos , Estudos Prospectivos , Neprilisina/antagonistas & inibidores , Resultado do Tratamento , Disfunção Cognitiva/tratamento farmacológico , Idoso de 80 Anos ou maisRESUMO
This systematic review and meta-analysis aimed to determine the association between the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and dementia onset as well as cognitive function in patients with diabetes mellitus. We comprehensively searched the MEDLINE, Embase, and CENTRAL databases to select relevant studies published up to August 2023. The use of SGLT-2 inhibitors significantly lowers dementia risk compared to SGLT-2i non-users (Hazard ratio: 0.68, 95 % CI: 0.50-0.92). Furthermore, our findings indicated a positive effect of SGLT-2 inhibitor use on cognitive function score improvement, as demonstrated by the standardized mean difference of 0.88 (95 % CI: 0.32-1.44), particularly among populations with mild cognitive impairment or dementia. This systematic review and meta-analysis indicate a potential role of SGLT-2 inhibitors in reducing the risk of dementia in patients with diabetes mellitus. These findings underscore the need for well-controlled large clinical trials and future research in this field.
Assuntos
Cognição , Demência , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Demência/epidemiologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/epidemiologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologiaRESUMO
BACKGROUND: Docosahexaenoic acid (DHA) is a component of neural tissue. Because its accretion into the brain is greatest during the final trimester of pregnancy, infants born before 29 weeks' gestation do not receive the normal supply of DHA. The effect of this deficiency on subsequent cognitive development is not well understood. METHODS: We assessed general intelligence at 5 years in children who had been enrolled in a trial of neonatal DHA supplementation to prevent bronchopulmonary dysplasia. In the previous trial, infants born before 29 weeks' gestation had been randomly assigned in a 1:1 ratio to receive an enteral emulsion that provided 60 mg of DHA per kilogram of body weight per day or a control emulsion from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first. Children from 5 of the 13 centers in the original trial were invited to undergo assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age. The primary outcome was the full-scale intelligence quotient (FSIQ) score. Secondary outcomes included the components of WPPSI. RESULTS: A total of 1273 infants underwent randomization in the original trial; of the 656 surviving children who had undergone randomization at the centers included in this follow-up study, 480 (73%) had an FSIQ score available - 241 in the DHA group and 239 in the control group. After imputation of missing data, the mean (±SD) FSIQ scores were 95.4±17.3 in the DHA group and 91.9±19.1 in the control group (adjusted difference, 3.45; 95% confidence interval, 0.38 to 6.53; P = 0.03). The results for secondary outcomes generally did not support that obtained for the primary outcome. Adverse events were similar in the two groups. CONCLUSIONS: In infants born before 29 weeks' gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding. (Funded by the Australian National Health and Medical Research Council and Nu-Mega Ingredients; N3RO Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.).
Assuntos
Displasia Broncopulmonar , Cognição , Ácidos Docosa-Hexaenoicos , Recém-Nascido Prematuro , Inteligência , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Austrália , Displasia Broncopulmonar/prevenção & controle , Suplementos Nutricionais/efeitos adversos , Ácidos Docosa-Hexaenoicos/deficiência , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Emulsões , Seguimentos , Recém-Nascido Prematuro/crescimento & desenvolvimento , Inteligência/efeitos dos fármacos , Nutrição Enteral , Escalas de Wechsler , Cognição/efeitos dos fármacosRESUMO
The systemic effects of the artificial sweetener sorbitol on older adult individuals have not been elucidated. We assessed the effects of sorbitol consumption on cognitive and gingival health in a mouse model. Aged mice were fed 5% sorbitol for 3 months before their behavior was assessed, and brain and gingival tissues were collected. Long-term sorbitol consumption inhibited gingival tissue aging in aged mice. However, it caused cognitive decline and decreased brain-derived neurotrophic factor (BDNF) in the hippocampus. Sorbitol consumption did not affect homeostatic function; however, it may exert effects within the brain, particularly in the hippocampus.
Assuntos
Envelhecimento , Cognição , Hipocampo , Sorbitol , Animais , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Sorbitol/farmacologia , Sorbitol/administração & dosagem , Camundongos , Cognição/efeitos dos fármacos , Masculino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Camundongos Endogâmicos C57BL , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/etiologiaRESUMO
OBJECTIVE: Exposure to heavy metals has been reported to be associated with impaired cognitive function, but the underlying mechanisms remain unclear. This pilot study aimed to identify key heavy metal elements associated with cognitive function and further explore the potential mediating role of metal-related DNA methylation. METHODS: Blood levels of arsenic, cadmium, lead, copper, manganese, and zinc and genome-wide DNA methylations were separately detected in peripheral blood in 155 older adults. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE). Least absolute shrinkage and selection operator penalized regression and Bayesian kernel machine regression were used to identify metals associated with cognitive function. An epigenome-wide association study examined the DNA methylation profile of the identified metal, and mediation analysis investigated its mediating role. RESULTS: The MMSE scores showed a significant decrease of 1.61 (95% confidence interval [CI]: -2.64, -0.59) with each 1 standard deviation increase in ln-transformed arsenic level; this association was significant in multiple-metal models and dominated the overall negative effect of 6 heavy metal mixture on cognitive function. Seventy-three differentially methylated positions were associated with blood arsenic (p < 1.0 × 10-5). The methylation levels at cg05226051 (annotated to TDRD3) and cg18886932 (annotated to GAL3ST3) mediated 24.8% and 25.5% of the association between blood arsenic and cognitive function, respectively (all p < 0.05). INTERPRETATION: Blood arsenic levels displayed a negative association with the cognitive function of older adults. This finding shows that arsenic-related DNA methylation alterations are critical partial mediators that may serve as potential biomarkers for further mechanism-related studies. ANN NEUROL 2024;96:87-98.
Assuntos
Cognição , Metilação de DNA , Epigenoma , Análise de Mediação , Metais Pesados , Humanos , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Feminino , Masculino , Metais Pesados/sangue , Idoso , Cognição/efeitos dos fármacos , Epigenoma/genética , Projetos Piloto , Arsênio/sangue , Arsênio/toxicidade , Estudo de Associação Genômica Ampla , Pessoa de Meia-Idade , Disfunção Cognitiva/genética , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/sangue , Idoso de 80 Anos ou mais , Testes de Estado Mental e DemênciaRESUMO
Chronic social isolation increases the risk of mental health problems, including cognitive impairments and depression. While subanesthetic ketamine is considered effective for cognitive impairments in patients with depression, the neural mechanisms underlying its effects are not well understood. Here we identified unique activation of the anterior insular cortex (aIC) as a characteristic feature in brain-wide regions of mice reared in social isolation and treated with (R)-ketamine, a ketamine enantiomer. Using fiber photometry recording on freely moving mice, we found that social isolation attenuates aIC neuronal activation upon social contact and that (R)-ketamine, but not (S)-ketamine, is able to counteracts this reduction. (R)-ketamine facilitated social cognition in social isolation-reared mice during the social memory test. aIC inactivation offset the effect of (R)-ketamine on social memory. Our results suggest that (R)-ketamine has promising potential as an effective intervention for social cognitive deficits by restoring aIC function.
Assuntos
Disfunção Cognitiva , Córtex Insular , Ketamina , Isolamento Social , Animais , Ketamina/farmacologia , Camundongos , Masculino , Córtex Insular/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Camundongos Endogâmicos C57BL , Memória/efeitos dos fármacos , Cognição/efeitos dos fármacos , Comportamento Social , Córtex Cerebral/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológicoRESUMO
Chronic stress causes cognitive deficits, such as impairments in episodic-like hippocampus-dependent memory. Stress regulates an opioid-related neuropeptide named Nociceptin/Orphanin FQ (N/OFQ), the ligand of the G protein-coupled receptor NOP. Since this peptide has deleterious effects on memory, we hypothesized that the N/OFQ system could be a mediator of the negative effects of stress on memory. Chronic stress was mimicked by chronic exposure to corticosterone (CORT). The NOP receptor was either acutely blocked using selective antagonists, or knocked-down specifically in the hippocampus using genetic tools. Long-term memory was assessed in the object recognition (OR) and object location (OL) paradigms. Acute injection of NOP antagonists before learning had a negative impact on memory in naive mice whereas it restored memory performances in the chronic stress model. This rescue was associated with a normalization of neuronal cell activity in the CA3 part of the hippocampus. Chronic CORT induced an upregulation of the N/OFQ precursor in the hippocampus. Knock-down of the NOP receptor in the CA3/Dentate Gyrus region prevented memory deficits in the CORT model. These data demonstrate that blocking the N/OFQ system can be beneficial for long-term memory in a neuroendocrine model of chronic stress. We therefore suggest that NOP antagonists could be useful for the treatment of memory deficits in stress-related disorders.
Assuntos
Corticosterona , Modelos Animais de Doenças , Hipocampo , Memória de Longo Prazo , Receptor de Nociceptina , Nociceptina , Peptídeos Opioides , Receptores Opioides , Estresse Psicológico , Animais , Receptores Opioides/metabolismo , Camundongos , Estresse Psicológico/metabolismo , Masculino , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Peptídeos Opioides/metabolismo , Memória de Longo Prazo/efeitos dos fármacos , Memória de Longo Prazo/fisiologia , Antagonistas de Entorpecentes/farmacologia , Camundongos Endogâmicos C57BL , Cognição/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/tratamento farmacológicoRESUMO
Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer's disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer's disease. However, there is currently no effective CypD inhibitor for Alzheimer's disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of â¼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer's disease mitochondrial and glycolytic bioenergetics in Alzheimer's disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer's disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer's disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer's disease- and amyloid-ß-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer's disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer's disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.
Assuntos
Doença de Alzheimer , Isoindóis , Mitocôndrias , Compostos Organosselênicos , Peptidil-Prolil Isomerase F , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptidil-Prolil Isomerase F/metabolismo , Animais , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos , Humanos , Cognição/efeitos dos fármacos , Azóis/farmacologia , Azóis/uso terapêutico , Ciclofilinas/metabolismo , Ciclofilinas/antagonistas & inibidores , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Masculino , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêuticoRESUMO
An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its proneurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3(-/-) mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging. PAPERCLIP:
Assuntos
Carbazóis/farmacologia , Avaliação Pré-Clínica de Medicamentos , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Fármacos Neuroprotetores/farmacologia , Envelhecimento/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carbazóis/química , Cognição/efeitos dos fármacos , Giro Denteado/citologia , Giro Denteado/fisiologia , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Fármacos Neuroprotetores/química , RatosRESUMO
Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-ß oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.
Assuntos
Envelhecimento/fisiologia , Encéfalo/citologia , Homeostase/efeitos dos fármacos , Microglia/efeitos dos fármacos , Ácido N-Acetilneuramínico/farmacologia , Fagocitose/efeitos dos fármacos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Cognição/efeitos dos fármacos , Cognição/fisiologia , Feminino , Homeostase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Ácido N-Acetilneuramínico/química , Fagocitose/genética , Análise de Sequência de RNA , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismoRESUMO
Tumor necrosis factor-α (TNF-α) is a pleiotropic, proinflammatory cytokine related to different neurodegenerative diseases, including Alzheimer's disease (AD). Although the linkage between increased TNF-α levels and AD is widely recognized, TNF-α-neutralizing therapies have failed to treat AD. Previous research has associated this with the antithetic functions of the two TNF receptors, TNF receptor 1, associated with inflammation and apoptosis, and TNF receptor 2 (TNFR2), associated with neuroprotection. In our study, we investigated the effects of specifically stimulating TNFR2 with a TNFR2 agonist (NewStar2) in a transgenic Aß-overexpressing mouse model of AD by administering NewStar2 in two different ways: centrally, via implantation of osmotic pumps, or systemically by intraperitoneal injections. We found that both centrally and systemically administered NewStar2 resulted in a drastic reduction in amyloid ß deposition and ß-secretase 1 expression levels. Moreover, activation of TNFR2 increased microglial and astrocytic activation and promoted the uptake and degradation of Aß. Finally, cognitive functions were also improved after NewStar2 treatment. Our results demonstrate that activation of TNFR2 mitigates Aß-induced cognitive deficits and neuropathology in an AD mouse model and indicates that TNFR2 stimulation might be a potential treatment for AD.
Assuntos
Doença de Alzheimer , Cognição , Receptores Tipo II do Fator de Necrose Tumoral , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/agonistas , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem without therapeutic options. Using the platinum-based chemotherapy cisplatin to model CICI, we revealed robust elevations in the adenosine A2A receptor (A2AR) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A2AR inhibition by the Food and Drug Administration-approved A2AR antagonist KW-6002 prevented cisplatin-induced impairments in neural progenitor proliferation and dendrite morphogenesis of adult-born neurons, while improving memory and anxiety-like behavior, without affecting tumor growth or cisplatin's antitumor activity. Collectively, our study identifies A2AR signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.