No abstract

The deregulation of brain cholesterol metabolism is typical in acute neuronal injury (such as stroke, brain trauma and epileptic seizures) and chronic neurodegenerative diseases (Alzheimer's disease). Since both conditions are characterized by excessive stimulation of glutamate receptors, we have here investigated to which extent excitatory neurotransmission plays a role in brain cholesterol homeostasis. We show that a short (30 min) stimulation of glutamatergic neurotransmission induces a small but significant loss of membrane cholesterol, which is paralleled by release to the extracellular milieu of the metabolite 24S-hydroxycholesterol. Consistent with a cause-effect relationship, knockdown of the enzyme cholesterol 24-hydroxylase (CYP46A1) prevented glutamate-mediated cholesterol loss. Functionally, the loss of cholesterol modulates the magnitude of the depolarization-evoked calcium response. Mechanistically, glutamate-induced cholesterol loss requires high levels of intracellular Ca 2 þ , a functional stromal interaction molecule 2 (STIM2) and mobilization of CYP46A1 towards the plasma membrane. This study underscores the key role of excitatory neurotransmission in the control of membrane lipid composition, and consequently in neuronal membrane organization and function.

J. Neurochem. (2011) 116, 747–755. Abstract It is well established that memory formation and retention involve the coordinated flow of information from the post‐synaptic site of particular neuronal populations to the nucleus, where short and long‐lasting modifications of gene expression occur. With age, mnemonic, motor and sensorial alterations occur, and it is believed that extra failures in the mechanisms used for memory formation and storage are the cause of neurodegenerative pathologies like Alzheimer’s disease. A prime candidate responsible for damage and loss of function during aging is the accumulation of reactive oxygen species, derived from normal oxidative metabolism. However, dysfunction in the aged brain is not paralleled by an increase in neuronal death, indicative that the brain is better suited to fight against the death signals generated from reactive oxygen species than against loss‐of‐function stimuli. A main aim of this laboratory is to understand how neurons perform and survive in the constitutive stress background represented by aging. In this report, we summarize our recent findings in relation to survival.

Cholesterol homeostasis in every tissue is maintained by the delicate mutual regulation between synthesis and catabolism in different cell types. In the mature brain, after myelination has ceased, cholesterol catabolism acquires special relevance to regulate the levels of this lipid, particularly in neurons, because of the general decline of the cholesterol synthesis rate in the brain. The limited synthesis essentially takes place in astrocytes, which have the ability to supply neurons with cholesterol via lipoproptein particles. ATP-binding cassette (ABC) transporters on the astrocyte's plasma membrane are in charge of exporting the synthetized cholesterol to the extracellular milieu. The brain apolipoproteins needed to assemble the lipoprotein particles (ApoE and ApoJ) are also produced and secreted by astrocytes. Ultimately, the lipoprotein particles that carry cholesterol are internalized into neurons after the interaction with surface lipoprotein receptors of the LRP and LDL families (Vitali et al., 2014; Zhang & Liu, 2015) (see Figure 1).Cholesterol synthesis in the brain involves the same molecular reactions than in the liver, being the initial precursor acetyl-CoA.The major regulatory check-point of the cholesterol synthesis is the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate by the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a known target of the statins. The transcription of this enzyme is controlled by sterol regulatory element-binding proteins (SREBPs), transcription factors that can bind an sterol-regulatory element (SRE) in the promoter region of the HMGCR gene. The SREBP family is integrated by three isoforms: SREBP-1a, SREBP-1c, and SREBP-2. Among them SREBP-2 is the most abundant in brain tissue (Camargo et al.,