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Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e. GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 ablation (GLUT11′GFAP mice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Importantly, GLUT11′GFAP mice did not present cognitive alterations. Mechanistically, we observed that GLUT1-ablated astrocytes exhibited increased insulin receptor-dependent ATP release, and both astrocyte insulin signalling and brain purinergic signalling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its ablation triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis and cognitive function.

Obesity and aging are becoming increasingly prevalent across the globe. It has been established that aging is the major risk factor for Alzheimer’s disease (AD), and it is becoming increasingly evident that obesity and the associated insulin resistance are also notably relevant risk factors. The biological plausibility of the link between high adiposity, insulin resistance, and dementia is central for understanding AD etiology, and to form bases for prevention efforts to decrease the disease burden. Several studies have demonstrated a strong association between short chain fatty acid receptor FFAR3 and insulin sensitivity. Interestingly, it has been recently established that FFAR3 mRNA levels are increased in early stages of the AD pathology, indicating that FFAR3 could play a key role in AD onset and progression. Indeed, in the present study we demonstrate that the ablation of the Ffar3 gene in Tg2576 mice prevents the development of cognitive deficiencies in advanced stages of the disease. Notably, this cognitive improvement is also maintained upon a severe metabolic challenge such as the exposure to high-fat diet (HFD) feeding. Moreover, FFAR3 deletion restores the brain hypermetabolism displayed by Tg2576 mice. Collectively, these data postulate FFAR3 as a potential novel target for AD.

Resumen Objetivos La enfermedad de Alzheimer (EA) es una enfermedad neurodegenerativa. La EA es la principal causa de demencia en el mundo, siendo el envejecimiento el principal factor de riesgo. Los criterios diagnósticos para la enfermedad de Alzheimer suelen basarse en datos clínicos. No obstante, es necesario establecer una definición biológica de la enfermedad de Alzheimer basada en biomarcadores que reflejen la neuropatología subyacente. Contenido El objetivo de esta revisión es presentar los resultados obtenidos en la medición de biomarcadores nuevos y ya conocidos en los fluidos biológicos o en neuroimágenes. Resumen Actualmente se emplean tres biomarcadores para el diagnóstico de la enfermedad de Alzheimer_Aβ42, t-Tau y p-Tau. El uso diagnóstico de biomarcadores en el líquido cefalorraquídeo (LCR) presenta algunas limitaciones debido a que la obtención invasiva mediante punción lumbar puede provocar efectos secundarios. La práctica más común en los centros clínicos es la medición en plasma o suero, ya que es mínimamente invasiva y, en consecuencia, se puede obtener y procesar con mayor facilidad. Las dos principales proteínas implicadas en el proceso patológico, Aβ y Tau, se pueden visualizar empleando técnicas de neuroimagen como la PET. Perspectivas Dado que está ampliamente aceptado que la enfermedad de Alzheimer comienza décadas antes de que se diagnostiquen los primeros síntomas clínicos, la detección de alteraciones biológicas previa a la aparición de la sintomatología clínica permitiría su diagnóstico precoz o incluso abriría la puerta a nuevas opciones terapéuticas.

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease. AD is the main cause of dementia worldwide and aging is the main risk factor for developing the illness. AD classical diagnostic criteria rely on clinical data. However, the development of a biological definition of AD using biomarkers that reflect the underling neuropathology is needed. Content The aim of this review is to describe the main outcomes when measuring classical and novel biomarkers in biological fluids or neuroimaging. Summary Nowadays, there are three classical biomarkers for the diagnosis of AD: Aβ42, t-Tau and p-Tau. The diagnostic use of cerebrospinal fluid biomarkers is limited due to invasive collection by lumbar puncture with potential side effects. Plasma/serum measurements are the gold standard in clinics, because they are minimally invasive and, in consequence, easily collected and processed. The two main proteins implicated in the pathological process, Aβ and Tau, can be visualized using neuroimaging techniques, such as positron emission tomography. Outlook As it is currently accepted that AD starts decades before clinical symptoms could be diagnosed, the opportunity to detect biological alterations prior to clinical symptoms would allow early diagnosis or even perhaps change treatment possibilities.

c-Jun N-terminal kinases (JNKs) are a family of protein kinases that can be activated by numerous stimuli and regulate a broad spectrum of biological processes in the Central Nervous System. JNK3, a specific isoform in the brain, have been shown to be involved in neurodegenerative conditions. Even though JNK over-activation has been observed in human brains affected with Alzheimer’s disease (AD), its role in AD pathology development is still unclear. One of the early regions of neuronal volume loss in AD is the Entorhinal Cortex (EC). Indeed, the loss of projections from EC to hippocampus (Hp) in the early phases of AD has raised the idea that the connection between EC and Hp could be deteriorated in AD. Thus, the main aim of the current work is to address if JNK3 overexpression in the EC could spread to the hippocampus, leading to cognitive deficiencies, similar to what occurs in early stages of AD. Data acquired in the current study suggest that JNK3 overexpression in the EC is also observed in the Hp and this leads to cognitive impairment. Moreover, pro-inflammatory cytokines expression and Tau immunoreactivity appeared to be increased both in the EC and Hp. Therefore, activation of inflammatory signaling and induction of Tau aberrant misfolding caused by JNK3 could be the underlying mechanism of the observed cognitive impairment. Altogether, JNK3 overexpression may disseminate from EC to Hp inducing cognitive dysfunction in vulnerable brain regions and may underlie the alterations observed in early stages of AD.

The brain is one of the most energy-consuming organs in the body. Satisfying such energy demand requires compartmentalized, cell-specific metabolic processes, known to be complementary and intimately coupled. Thus, the brain relies on thoroughly orchestrated energy-obtaining agents, processes and molecular features, such as the neurovascular unit, the astrocyte–neuron metabolic coupling, and the cellular distribution of energy substrate transporters. Importantly, early features of the aging process are determined by the progressive perturbation of certain processes responsible for adequate brain energy supply, resulting in brain hypometabolism. These age-related brain energy alterations are further worsened during the prodromal stages of neurodegenerative diseases, namely Alzheimer’s disease (AD), preceding the onset of clinical symptoms, and are anatomically and functionally associated with the loss of cognitive abilities. Here, we focus on concrete neuroenergetic features such as the brain’s fueling by glucose and lactate, the transporters and vascular system guaranteeing its supply, and the metabolic interactions between astrocytes and neurons, and on its neurodegenerative-related disruption. We sought to review the principles underlying the metabolic dimension of healthy and AD brains, and suggest that the integration of these concepts in the preventive, diagnostic and treatment strategies for AD is key to improving the precision of these interventions.