Biology subjects

Casals, N.

Publications and source records attributed to Casals, N..

3 recordsLinked to original sources

bioRxiv2025

SSAO-mediated decrease of endothelial BDNF release affects neuronal GluA1 and PSD95 expression: a peripheral mechanism inducing NVU and CNS disturbances

Dysfunction of the vascular system contributes to brain damage and neurodegeneration, and cerebral amyloid angiopathy (CAA) can be identified in a high percentage of Alzheimer disease (AD) brains. Blood-brain barrier (BBB) alterations can affect communication and signalling between neurovascular unit (NVU) components through changes in the release of angioneurins, among others. The two-hit vascular hypothesis of AD suggests that chronic vascular risk factors cause an early damage to the brain microvasculature (hit 1) triggering a cascade of events that leads to amyloid β-peptide (Aβ) accumulation in the brain and precipitating the Aβ-dependent pathway of neurodegeneration (hit 2). The vascular enzyme and adhesion molecule SSAO/VAP-1 plays an important role in cerebrovascular dysfunction and vascular Aβ aggregation, acting as an active player in the first of the two-hits. We generated a new NVU in vitro model to study the role of SSAO/VAP-1 on the BBB dysfunction and its effects on neurons in an AD context. We focused on the release of key angioneurins for synaptic plasticity and neuronal survival, highly compromised in AD. Our results show that SSAO/VAP-1 expression, together with the addition of Aβ1-40peptide containing the Dutch mutation (used to mimic CAA condition; AβD), to cerebral endothelial cells synergistically alter the release of vascular BDNF. This alteration subsequently affects the expression of synaptic markers PSD95 and GluA1 in cortical neurons. Moreover, GluA1 and PSD95-positive neurons present reduced immunolabeling intensity of these markers when low levels of vascular BDNF are present. These results reveal vascular BDNF as a possible key element in the sensitization to Aβ due to SSAO/VAP-1 expression, impacting negatively on glutamatergic synaptic and NVU function.HighlightsSSAO/VAP-1 expression alters BBB decreasing ZO-1, VE-Cadherin and Claudin-5 levels.SSAO/VAP-1 expression alters the release of vascular angioneurin BDNF.SSAO/VAP-1 and AβD decrease synaptic protein levels affecting glutamatergic neurons.Endothelial BDNF decrease induced by SSAO/VAP-1 and AβD alters glutamatergic neurons.

neuroscience↗

bioRxiv2024

BETA-HYDROXYBUTYRATE COUNTERACTS THE DELETERIOUS EFFECTS OF A SATURATED HIGH-FAT DIET ON SYNAPTIC AMPA RECEPTORS AND COGNITIVE PERFORMANCE

The ketogenic diet, characterized by high fat and low carbohydrates, has gained popularity not only as a strategy for managing body weight but also for its efficacy in delaying cognitive decline associated with neurodegenerative diseases and the aging process. Since this dietary approach stimulates the livers production of ketone bodies, primarily {beta}-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons, we investigated whether BHB could mitigate impaired AMPA receptor trafficking, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as saturated fatty acids. Here, we observe that, in cultured primary cortical neurons, exposure to palmitic acid (200M) decreased surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids, such as oleic acid and {omega}-3 docosahexaenoic acid (200M), and BHB (5mM) increased them. Furthermore, BHB countered the adverse effects of palmitic acid on synaptic GluA1 levels in hippocampal neurons, as well as excitability and plasticity in hippocampal slices. Additionally, daily intragastric administration of BHB (100 mg/kg/day) for two months reversed cognitive impairment induced by a saturated high-fat diet (49% of calories from fat) in a mouse experimental model of obesity. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptors abundance, synaptic function and neuroplasticity, shedding light on the potential use of BHB to delay cognitive impairments associated with metabolic diseases.

neuroscience↗

bioRxiv2024

DEFICIENCY OF THE NUTRIENT SENSOR CPT1c IN SF1 NEURONS DISRUPTS THE ENDOCANNABINOID SYSTEM RESULTING IN COMPROMISED SATIETY AND FUEL SELECTION UPON FAT INTAKE

The SF1 neurons of the ventromedial hypothalamus (VMH) are pivotal in governing body weight and adiposity, particularly in response to a high-fat diet (HFD). Previous studies have shown that the activation of SF1 neurons induces satiety, increases energy expenditure, and promotes the preferential use of fats as energy substrate. Furthermore, SF1 neurons are necessary for recovering from insulin-induced hypoglycemia. Here we demonstrate the essential role of the nutritional sensor CPT1c in the activation of SF1 neurons by dietary fats. Mice deficient in CPT1C in SF1 neurons (SF1-CPT1c-KO) are unable to adjust their caloric intake during the initial exposure to a HFD. This is associated with an impaired metabolic transition in the liver, muscle, and adipose tissue, despite a normal response to a glucose or insulin challenge. During chronic HFD exposure, SF1-CPT1c-KO mice are more prone to obesity and glucose intolerance than controls. CPT1c deficiency in SF1 neurons also leads to alterations in hypothalamic endocannabinoid levels and their metabolism. Our findings posit CPT1C in SF1 neurons as a sensor for dietary fats, regulating satiety responses and nutrient partitioning likely through the modulation of the endocannabinoid system.

neuroscience↗