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1.
Brain Behav Immun ; 119: 286-300, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38608739

RESUMO

Alzheimer's disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimer's disease onset and progression. Characterizing the initial phase of Alzheimer's disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used the AppNL-G-F knock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimer's disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis- and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory network's functionality. These results suggest that the early alteration of microglia dynamics could be a pivotal event in the progression of Alzheimer's disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus.


Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Progressão da Doença , Hipocampo , Camundongos Transgênicos , Microglia , Placa Amiloide , Animais , Microglia/metabolismo , Microglia/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Camundongos , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Peptídeos beta-Amiloides/metabolismo , Masculino , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Interneurônios/metabolismo , Interneurônios/patologia
2.
Int J Mol Sci ; 22(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34576302

RESUMO

The activation of the brain renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cognition. While the brain RAS has been studied before in the context of hypertension, little is known about its role and regulation in relation to neuronal function and its modulation. Adequate blood flow to the brain as well as proper clearing of metabolic byproducts become crucial in the presence of neurodegenerative disorders such as Alzheimer's disease (AD). RAS inhibition (RASi) drugs that can cross into the central nervous system have yielded unclear results in improving cognition in AD patients. Consequently, only one RASi therapy is under consideration in clinical trials to modify AD. Moreover, the role of non-genetic factors such as hypercholesterolemia in the pathophysiology of AD remains largely uncharacterized, even when evidence exists that it can lead to alteration of the RAS and cognition in animal models. Here we revise the evidence for the function of the brain RAS in cognition and AD pathogenesis and summarize the evidence that links it to hypercholesterolemia and other risk factors. We review existent medications for RASi therapy and show research on novel drugs, including small molecules and nanodelivery strategies that can target the brain RAS with potential high specificity. We hope that further research into the brain RAS function and modulation will lead to innovative therapies that can finally improve AD neurodegeneration.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Sistema Renina-Angiotensina , Doença de Alzheimer/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico
3.
Sci Adv ; 10(4): eadj1354, 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38266095

RESUMO

The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24S-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced CYP46A1 levels are observed in Alzheimer's disease (AD). In this study, we report that CYP46A1 overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions. In contrast, age-matched CYP46A1 overexpressing males show anxiety-like behavior, worsened memory, and elevated levels of 5α-dihydrotestosterone in the hippocampus. We report that, in neurons, 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. CYP46A1 overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Last, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of patients with AD and found that 24OH negatively correlates with neurodegeneration markers only in women. We suggest that CYP46A1 activation is a valuable pharmacological target for enhancing estrogen signaling in women at risk of developing neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Transtornos da Memória , Masculino , Feminino , Humanos , Animais , Camundongos , Idoso , Colesterol 24-Hidroxilase , Transtornos da Memória/etiologia , Colesterol , Cognição , Doença de Alzheimer/genética , Estrogênios
4.
Brain Commun ; 5(5): fcad228, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37680670

RESUMO

Alzheimer's disease is a multifactorial disorder with large heterogeneity. Comorbidities such as hypertension, hypercholesterolaemia and diabetes are known contributors to disease progression. However, less is known about their mechanistic contribution to Alzheimer's pathology and neurodegeneration. The aim of this study was to investigate the relationship of several biomarkers related to risk mechanisms in Alzheimer's disease with the well-established Alzheimer's disease markers in a memory clinic population without common comorbidities. We investigated 13 molecular markers representing key mechanisms underlying Alzheimer's disease pathogenesis in CSF from memory clinic patients without diagnosed hypertension, hypercholesterolaemia or diabetes nor other neurodegenerative disorders. An analysis of covariance was used to compare biomarker levels between clinical groups. Associations were analysed by linear regression. Two-step cluster analysis was used to determine patient clusters. Two key markers were analysed by immunofluorescence staining in the hippocampus of non-demented control and Alzheimer's disease individuals. CSF samples from a total of 90 participants were included in this study: 30 from patients with subjective cognitive decline (age 62.4 ± 4.38, female 60%), 30 with mild cognitive impairment (age 65.6 ± 7.48, female 50%) and 30 with Alzheimer's disease (age 68.2 ± 7.86, female 50%). Angiotensinogen, thioredoxin-1 and interleukin-15 had the most prominent associations with Alzheimer's disease pathology, synaptic and axonal damage markers. Synaptosomal-associated protein 25 kDa and neurofilament light chain were increased in mild cognitive impairment and Alzheimer's disease patients. Grouping biomarkers by biological function showed that inflammatory and survival components were associated with Alzheimer's disease pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In the data-driven analysis, two patient clusters were identified: Cluster 1 had increased CSF markers of oxidative stress, vascular pathology and neuroinflammation and was characterized by elevated synaptic and axonal damage, compared with Cluster 2. Clinical groups were evenly distributed between the clusters. An analysis of post-mortem hippocampal tissue showed that compared with non-demented controls, angiotensinogen staining was higher in Alzheimer's disease and co-localized with phosphorylated-tau. The identification of biomarker-driven endophenotypes in cognitive disorder patients further highlights the biological heterogeneity of Alzheimer's disease and the importance of tailored prevention and treatment strategies.

5.
J Neuroimmune Pharmacol ; 18(3): 529-550, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37698780

RESUMO

Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer's disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In this study, we demonstrate that the specific SIRT2 inhibitor, the compound 33i, does not exhibit genotoxic or mutagenic properties. Moreover, pharmacological treatment with 33i, improved cognitive dysfunction and long-term potentiation, reducing amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of the inflammatory cytokines IL-1ß, TNF, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. The analysis of human samples revealed that SIRT2 is increased in the brain but not in the serum of AD patients. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its pharmacological inhibition at the periphery would not be recommended and the systemic adverse side effects should be considered. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Sirtuína 2 , Animais , Humanos , Camundongos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/patologia , Camundongos Transgênicos , Sirtuína 2/antagonistas & inibidores , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia
6.
Aging (Albany NY) ; 13(11): 14729-14744, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078751

RESUMO

The potential harmful effects of polypharmacy (concurrent use of 5 or more drugs) are difficult to investigate in an experimental design in humans. Moreover, there is a lack of knowledge on sex-specific differences on the outcomes of multiple-drug use. The present study aims to investigate the effects of an eight-week exposure to a regimen of five different medications (metoprolol, paracetamol, aspirin, simvastatin and citalopram) in young adult female mice. Polypharmacy-treated animals showed significant impairment in object recognition and fear associated contextual memory, together with a significant reduction of certain hippocampal proteins involved in pathways necessary for the consolidation of these types of memories, compared to animals with standard diet. The impairments in explorative behavior and spatial memory that we reported previously in young adult male mice administered the same polypharmacy regimen were not observed in females in the current study. Therefore, the same combination of medications induced different negative outcomes in young adult male and female mice, causing a significant deficit in non-spatial memory in female animals. Overall, this study strongly supports the importance of considering sex-specific differences in designing safer and targeted multiple-drug therapies.


Assuntos
Envelhecimento/fisiologia , Cognição/fisiologia , Polimedicação , Animais , Ansiedade/patologia , Comportamento Animal , Proteínas Sanguíneas/metabolismo , Peso Corporal , Dieta , Comportamento de Ingestão de Líquido , Comportamento Alimentar , Feminino , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Atividade Motora , Memória Espacial , Fatores de Tempo
7.
Aging (Albany NY) ; 12(11): 10147-10161, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32445552

RESUMO

A major challenge in the health care system is the lack of knowledge about the possible harmful effects of multiple drug treatments in old age. The present study aims to characterize a mouse model of polypharmacy, in order to investigate whether long-term exposure to multiple drugs could lead to adverse outcomes. To this purpose we selected five drugs from the ten most commonly used by older adults in Sweden (metoprolol, paracetamol, aspirin, simvastatin and citalopram). Five-month-old wild type male mice were fed for eight weeks with control or polypharmacy diet. We report for the first time that young adult polypharmacy-treated mice showed a significant decrease in exploration and spatial working memory compared to the control group. This memory impairment was further supported by a significant reduction of synaptic proteins in the hippocampus of treated mice. These novel results suggest that already at young adult age, use of polypharmacy affects explorative behavior and synaptic functions. This study underlines the importance of investigating the potentially negative outcomes from concomitant administration of different drugs, which have been poorly explored until now. The mouse model proposed here has translatable findings and can be applied as a useful tool for future studies on polypharmacy.


Assuntos
Comportamento Exploratório/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Polimedicação , Sinapses/efeitos dos fármacos , Adulto , Animais , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Masculino , Transtornos da Memória/diagnóstico , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Camundongos , Fatores de Risco , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Sinapses/fisiologia
8.
Neurochem Int ; 126: 74-85, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30633953

RESUMO

Antinociception caused by cannabinoids may have a partial peripheral origin in addition to its central site of action. In fact, we have observed that anandamide selectively and reversibly inhibits GABAA receptors of putative nociceptive neurons of mouse trigeminal sensory ganglia via CB1 receptor activation to inhibit adenylyl cyclase and decrease cAMP with downstream posttranslational alterations. Since cannabinoids are often used chronically, we studied changes in cAMP levels and GABA-mediated currents of trigeminal neurons following 24 h application of anandamide (0.5 µM) or the synthetic cannabinoid WIN 55,212-2 (5 µM). With this protocol GABA responses were similar to control despite persistent fall in cAMP levels. Inhibition by WIN 55,212-2 of GABA effects recovered after 30 min washout and was not associated with changes in CB1 receptor expression, indicating lack of CB1 receptor inactivation and transient loss of negative coupling between CB1 receptors and GABAA receptors. The phosphodiesterase inhibitor rolipram (100 µM; 24 h) enhanced cAMP levels and GABA-mediated currents, suggesting GABAA receptors were sensitive to persistent upregulation via cAMP. While the adenylyl cyclase activator forskolin (1-20 µM) facilitated cAMP levels and GABA currents following 30 min application, this action was lost after 24 h in line with the drug limited lifespan. The PKA inhibitor PKI 14-22 (10 µM) increased cAMP without changing GABA currents. These data indicate that modulation of GABAA receptors by intracellular cAMP could be lost following persistent application of cannabinoids. Thus, these observations provide an insight into the waning antinociceptive effects of these compounds.


Assuntos
Canabinoides/administração & dosagem , AMP Cíclico/metabolismo , Receptores de GABA-A/metabolismo , Células Receptoras Sensoriais/metabolismo , Gânglio Trigeminal/metabolismo , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Esquema de Medicação , Camundongos , Camundongos Endogâmicos C57BL , Células Receptoras Sensoriais/efeitos dos fármacos , Fatores de Tempo , Gânglio Trigeminal/efeitos dos fármacos
9.
Neuropharmacology ; 131: 39-50, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29225040

RESUMO

Endocannabinoids are suggested to control pain, even though their clinical use is not fully validated and the underlying mechanisms are incompletely understood. To clarify the targets of endocannabinoid actions, we studied how activation of the endocannabinoid CB1 receptor (CB1R) affects neuronal responses in two in vitro preparations of rodents, namely the trigeminal sensory ganglion (TG) in culture and a coronal slice of the cerebral cortex. On TG small-medium size neurons, we tested whether submicromolar concentrations of the endogenous CB1R agonist anandamide (AEA) modulated inhibitory GABAA receptors and excitatory ATP-gated P2X3 receptors. AEA reversibly depressed GABA-mediated membrane currents without altering P2X3 receptor responses. The AEA antagonism was non-competitive, prevented by the CB1R antagonist AM-251, mimicked by the other cannabinoids 2-arachidonylglycerol and WIN 55,212-2, and insensitive to TRPV1 blocker capsazepine. AEA inhibited the potentiation of GABAergic responses by the cAMP activator forskolin, in line with the canonical inhibition of cAMP synthesis by CB1Rs. In the cerebral cortex, AEA or WIN 55,212-2 did not affect electrically-evoked local field potentials or characteristics of cortical spreading depolarization (CSD) elicited by high potassium application. The GABAA receptor blocker gabazine, however, strongly enhanced field potentials without affecting CSD properties, suggesting that CSD was not dominantly controlled by GABAergic mechanisms. Our data propose that, despite the widespread expression of CB1Rs peripherally and centrally, the functional effects of AEA are region-specific and depend on CB1R coupling to downstream effectors. Future studies concerned with the mechanisms of AEA analgesia should perhaps be directed to discrete subcortical nuclei processing trigeminal inputs.


Assuntos
Córtex Cerebral/citologia , Endocanabinoides/metabolismo , Células Receptoras Sensoriais/metabolismo , Gânglio Trigeminal/citologia , Animais , Animais Recém-Nascidos , Ácidos Araquidônicos/farmacologia , Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Endocanabinoides/farmacologia , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Glicerídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Naftalenos/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Ratos , Ratos Wistar , Células Receptoras Sensoriais/efeitos dos fármacos
10.
Neuroscience ; 351: 47-64, 2017 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-28363781

RESUMO

Transgenic knock-in (KI) mice that express CaV2.1 channels containing an R192Q gain-of-function mutation in the α1A subunit known to cause familial hemiplegic migraine type-1 in patients, exhibit key disease characteristics and provide a useful tool to investigate pathophysiological mechanisms of pain transduction. Previously, KI trigeminal sensory neurons were shown to exhibit constitutive hyperexcitability due to up-regulation of ATP-gated P2X3 receptors that trigger spike activity at a more negative threshold. This implies that intrinsic neuronal conductances may shape action potential generation in response to ATP, which could act as a mediator of migraine headache. Here we investigated whether the hyperpolarization-activated conductance Ih, mediated by hyperpolarization activated cyclic nucleotide-gated channels (HCN), contributes to sub-threshold behavior and firing in wild-type (WT) and KI trigeminal ganglia (TG) neurons. Whereas most WT and KI trigeminal neurons expressed Ih current, blocked by the specific inhibitor ZD7288, it was smaller in KI neurons despite similar activation and deactivation kinetics. HCN1 and HCN2 were the most abundantly expressed subunits in TG, both in situ and in culture. In KI TG neurons, HCN2 subunits were predominantly present in the cytoplasm, not at the plasma membrane, likely accounting for the smaller Ih of such cells. ZD7288 hyperpolarized the membrane potential, thereby raising the firing threshold, and prolonging the spike trajectory to generate fewer spikes due to P2X3 receptor activation. The low amplitude of Ih in KI TG neurons suggests that down-regulation of Ih current in sub-threshold behavior acts as a compensatory mechanism to limit sensory hyperexcitability, manifested under certain stressful stimuli.


Assuntos
Ataxia Cerebelar/fisiopatologia , Transtornos de Enxaqueca/fisiopatologia , Células Receptoras Sensoriais/efeitos dos fármacos , Gânglio Trigeminal/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Ataxia Cerebelar/induzido quimicamente , Ataxia Cerebelar/genética , Ataxia Cerebelar/metabolismo , Modelos Animais de Doenças , Técnicas de Introdução de Genes/métodos , Potenciais da Membrana/efeitos dos fármacos , Camundongos Transgênicos , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/metabolismo , Pirimidinas/farmacologia , Receptores Purinérgicos P2X3/genética , Receptores Purinérgicos P2X3/metabolismo , Células Receptoras Sensoriais/metabolismo , Gânglio Trigeminal/metabolismo
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