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1.
J Neurochem ; 165(6): 809-826, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36444683

RESUMEN

Key pathological features of Alzheimer's disease (AD) include build-up of amyloid ß (Aß), which promotes synaptic abnormalities and ultimately leads to neuronal cell death. Metabolic dysfunction is known to influence the risk of developing AD. Impairments in the leptin system have been detected in AD patients, which has fuelled interest in targeting this system to treat AD. Increasing evidence supports pro-cognitive and neuroprotective actions of leptin and these beneficial effects of leptin are mirrored by a bioactive leptin fragment (leptin116-130 ). Here we extend these studies to examine the potential cognitive enhancing and neuroprotective actions of 8 six-amino acid peptides (hexamers) derived from leptin116-130 . In this study, we show that four of the hexamers (leptin116-121, 117-122, 118-123 and 120-125 ) replicate the ability of leptin to promote α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and facilitate hippocampal synaptic plasticity. Moreover, the pro-cognitive effects of the hexamers were verified in behavioural studies, with the administration of leptin117-122 enhancing performance in episodic memory tasks. The bioactive hexamers replicated the neuroprotective actions of leptin by preventing the acute hippocampal synapto-toxic effects of Aß, and the chronic effects of Aß on neuronal cell viability, Aß seeding and tau phosphorylation. These findings provide further evidence to support leptin and leptin-derived peptides as potential therapeutics for AD.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Humanos , Animales , Péptidos beta-Amiloides/metabolismo , Receptores AMPA/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología , Leptina/farmacología , Enfermedad de Alzheimer/metabolismo , Plasticidad Neuronal/fisiología , Hipocampo/metabolismo , Modelos Animales de Enfermedad
2.
Cereb Cortex ; 27(10): 4769-4782, 2017 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-27600840

RESUMEN

A key pathology of Alzheimer's disease (AD) is amyloid ß (Aß) accumulation that triggers synaptic impairments and neuronal death. Metabolic disruption is common in AD and recent evidence implicates impaired leptin function in AD. Thus the leptin system may be a novel therapeutic target in AD. Indeed, leptin has cognitive enhancing properties and it prevents the aberrant effects of Aß on hippocampal synaptic function and neuronal viability. However, as leptin is a large peptide, development of smaller leptin-mimetics may be the best therapeutic approach. Thus, we have examined the cognitive enhancing and neuroprotective properties of known bioactive leptin fragments. Here we show that the leptin (116-130) fragment, but not leptin (22-56), mirrored the ability of leptin to promote AMPA receptor trafficking to synapses and facilitate activity-dependent hippocampal synaptic plasticity. Administration of leptin (116-130) also mirrored the cognitive enhancing effects of leptin as it enhanced performance in episodic-like memory tests. Moreover, leptin (116-130) prevented hippocampal synaptic disruption and neuronal cell death in models of amyloid toxicity. These findings establish further the importance of the leptin system as a therapeutic target in AD.


Asunto(s)
Cognición/efectos de los fármacos , Hipocampo/metabolismo , Leptina/farmacología , Fragmentos de Péptidos/farmacología , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Cognición/fisiología , Humanos , Leptina/metabolismo , Memoria/efectos de los fármacos , Memoria/fisiología , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Fragmentos de Péptidos/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/fisiología
3.
Front Endocrinol (Lausanne) ; 12: 697445, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34975743

RESUMEN

Aim: We evaluated the efficacy of a novel brain permeable "metformin-like" AMP-activated protein kinase activator, R481, in regulating glucose homeostasis. Materials and Methods: We used glucose sensing hypothalamic GT1-7 neuronal cells and pancreatic αTC1.9 α-cells to examine the effect of R481 on AMPK pathway activation and cellular metabolism. Glucose tolerance tests and hyperinsulinemic-euglycemic and hypoglycemic clamps were used in Sprague-Dawley rats to assess insulin sensitivity and hypoglycemia counterregulation, respectively. Results: In vitro, we demonstrate that R481 increased AMPK phosphorylation in GT1-7 and αTC1.9 cells. In Sprague-Dawley rats, R481 increased peak glucose levels during a glucose tolerance test, without altering insulin levels or glucose clearance. The effect of R481 to raise peak glucose levels was attenuated by allosteric brain permeable AMPK inhibitor SBI-0206965. This effect was also completely abolished by blockade of the autonomic nervous system using hexamethonium. During hypoglycemic clamp studies, R481 treated animals had a significantly lower glucose infusion rate compared to vehicle treated controls. Peak plasma glucagon levels were significantly higher in R481 treated rats with no change to plasma adrenaline levels. In vitro, R481 did not alter glucagon release from αTC1.9 cells, but increased glycolysis. Non brain permeable AMPK activator R419 enhanced AMPK activity in vitro in neuronal cells but did not alter glucose excursion in vivo. Conclusions: These data demonstrate that peripheral administration of the brain permeable "metformin-like" AMPK activator R481 increases blood glucose by activation of the autonomic nervous system and amplifies the glucagon response to hypoglycemia in rats. Taken together, our data suggest that R481 amplifies the counterregulatory response to hypoglycemia by a central rather than a direct effect on the pancreatic α-cell. These data provide proof-of-concept that central AMPK could be a target for future drug development for prevention of hypoglycemia in diabetes.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Sistema Nervioso Autónomo/efectos de los fármacos , Glucemia/efectos de los fármacos , Hipoglucemia/metabolismo , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Animales , Sistema Nervioso Autónomo/fisiología , Benzamidas/farmacología , Glucemia/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células Cultivadas , Hipoglucemia/patología , Hipoglucemia/fisiopatología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Permeabilidad/efectos de los fármacos , Piperidinas/farmacología , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley
4.
Alzheimers Dement (N Y) ; 6(1): e12078, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32864416

RESUMEN

BACKGROUND: Stroke/thromboembolic events, infections, and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events. METHODS: Whole transcriptome signatures were generated for SH-SY5Y cells treated with amisulpride, risperidone, and volinanserin using RNA sequencing. Bioinformatic analysis was performed that scored the association between antipsychotic signatures and expression data from 415,252 samples in the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) repository. RESULTS: Atherosclerosis, venous thromboembolism, and influenza NCBI GEO-derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (eg, brain derived neurotrophic factor [BDNF], platelet derived growth factor receptor [PDGFR]-beta, tumor necrosis factor [TNF], transforming growth factor [TGF]-beta, selenoamino acid metabolism, and influenza infection). CONCLUSIONS: These findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events.

5.
Mol Endocrinol ; 29(1): 3-13, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25470238

RESUMEN

The peripheral actions of the metabolic hormones, leptin and insulin, are well documented. However, the functions of these hormones are not restricted to the periphery because evidence is growing that both leptin and insulin can readily cross the blood-brain barrier and have widespread central actions. The hippocampus in particular expresses high levels of both insulin and leptin receptors as well as key components of their associated signaling cascades. Moreover, recent studies indicate that both hormones are potential cognitive enhancers. Indeed, it has been demonstrated that both leptin and insulin markedly influence key cellular events that underlie hippocampal learning and memory including activity-dependent synaptic plasticity and the trafficking of glutamate receptors to and away from hippocampal synapses. The hippocampal formation is also a prime site for the neurodegenerative processes that occur during Alzheimer's disease, and impairments in either leptin or insulin function have been linked to central nervous system-driven diseases like Alzheimer's disease. Thus, the capacity of the metabolic hormones, leptin and insulin, to regulate hippocampal synaptic function has significant implications for normal brain function and also central nervous system-driven disease.


Asunto(s)
Insulina/metabolismo , Leptina/metabolismo , Enfermedades Neurodegenerativas/patología , Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Barrera Hematoencefálica/efectos de los fármacos , Hipocampo/fisiología , Humanos , Receptores de Leptina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/fisiología
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