a b s t r a c tSimple sphingolipids such as ceramide and sphingomyelin (SM) as well as more complex glycosphingolipids play very important roles in cell function under physiological conditions and during disease development and progression. Sphingolipids are particularly abundant in the nervous system. Due to their amphiphilic nature they localize to cellular membranes and many of their roles in health and disease result from membrane reorganization and from lipid interaction with proteins within cellular membranes. In this review we discuss some of the functions of sphingolipids in processes that entail cellular membranes and their role in neurodegenerative diseases, with an emphasis on SM, ceramide and gangliosides.

Extracellular accumulation of ␤-amyloid peptide (A␤) has been linked to the development of Alzheimer disease. The importance of intraneuronal A␤ has been recognized more recently. Although considerable evidence indicates that extracellular A␤ contributes to the intracellular pool of A␤, the mechanisms involved in A␤ uptake by neurons are poorly understood. We examined the molecular mechanisms involved in A␤-(1-42) internalization by primary neurons in the absence of apolipoprotein E. We demonstrated that A␤-(1-42) is more efficiently internalized by axons than by cell bodies of sympathetic neurons, suggesting that A␤-(1-42) uptake might be mediated by proteins enriched in the axons. Although the acetylcholine receptor ␣7nAChR, previously suggested to be involved in A␤ internalization, is enriched in axons, our results indicate that it does not mediate A␤-(1-42) internalization. Moreover, receptors of the low density lipoprotein receptor family are not essential for A␤-(1-42) uptake in the absence of apolipoprotein E because receptor-associated protein had no effect on A␤ uptake. By expressing the inactive dynamin mutant dynK44A and the clathrin hub we found that A␤-(1-42) internalization is independent of clathrin but dependent on dynamin, which suggests an endocytic pathway involving caveolae/lipid rafts. Confocal microscopy studies showing that A␤ did not colocalize with the early endosome marker EEA1 further support a clathrin-independent mechanism. The lack of co-localization of A␤ with caveolin in intracellular vesicles and the normal uptake of A␤ by neurons that do not express caveolin indicate that A␤ does not require caveolin either. Instead partial co-localization of A␤-(1-42) with cholera toxin subunit B and sensitivity to reduction of cellular cholesterol and sphingolipid levels suggest a caveolae-independent, raft-mediated mechanism. Understanding the molecular events involved in neuronal A␤ internalization might identify potential therapeutic targets for Alzheimer disease.In brains of individuals with Alzheimer disease (AD), 2 ␤-amyloid peptide (A␤) aggregates and accumulates as toxic fibrils in neuritic plaques and toxic soluble oligomers (1). A␤ is a 39 -43-amino acid peptide derived from the proteolytic cleavage of the amyloid precursor protein (APP) (2). The amyloid cascade hypothesis predicts that a gradual increase of A␤-(1-42) levels in brain interstitial fluid (3, 4) may lead to A␤ oligomerization and eventually to A␤ fibrillization (5). Current evidence indicates that intraneuronal accumulation of A␤ is an early pathological biomarker for the onset of AD and may contribute to the cascade of neurodegenerative events (6). The observation that cortical neurons that accumulate A␤-(1-42) in brains of Down syndrome patients are apoptotic (7, 8) provided additional indications of the importance of intracellular A␤ (7,8). Furthermore, microinjection of A␤-(1-42) or cDNA encoding A␤-(1-42) in cultured human neurons resulted in neurotoxicity (9). Besides, in the triple transgenic mouse model for AD t...

Glia modulate neuronal activity by releasing transmitters in a process called gliotransmission. The role of this process in controlling the activity of neuronal networks underlying motor behavior is unknown. ATP features prominently in gliotransmission; it also contributes to the homeostatic ventilatory response evoked by low oxygen through mechanisms that likely include excitation of preBötzinger complex (preBötC) neural networks, brainstem centers critical for breathing. We therefore inhibited glial function in rhythmically active inspiratory networks in vitro to determine whether glia contribute to preBötC ATP sensitivity. Glial toxins markedly reduced preBötC responses to ATP, but not other modulators. Furthermore, since preBötC glia responded to ATP with increased intracellular Ca 2ϩ and glutamate release, we conclude that glia contribute to the ATP sensitivity of preBötC networks, and possibly the hypoxic ventilatory response. Data reveal a role for glia in signal processing within brainstem motor networks that may be relevant to similar networks throughout the neuraxis.

Cholesterol can be detrimental or vital, and must be present in the right place at the right time and in the right amount. This is well known in the heart and the vascular system. However, in the CNS cholesterol is still an enigma, although several of its fundamental functions in the brain have been identified. Brain cholesterol has attracted additional attention owing to its close connection to ApoE, a key polymorphic transporter of extracellular cholesterol in humans. Indeed, both cholesterol and ApoE are so critical to fundamental activities of the brain, that the brain regulates their synthesis autonomously. Yet, similar control mechanisms of ApoE and cholesterol homeostasis may exist on either sides of the blood–brain barrier. One indication is that the APOE ε4 allele is associated with hypercholesterolemia and a proatherogenic profile on the vascular side and with increased risk of Alzheimer’s disease on the CNS side. In this review, we draw attention to the association between cholesterol and ApoE in the aging and diseased brain, and to the behavior of the ApoE4 protein at the molecular level. The attempt to correlate in vivo and in vitro observations is challenging but crucial for developing future strategies to address ApoE-related aberrations in cholesterol metabolism selectively in the brain.

In the brain, the amyloid β peptide (Aβ) exists extracellularly and inside neurons. The intracellular accumulation of Aβ in Alzheimer's disease brain has been questioned for a long time. However, there is now sufficient strong evidence indicating that accumulation of Aβ inside neurons plays an important role in the pathogenesis of Alzheimer's disease. Intraneuronal Aβ originates from intracellular cleavage of APP and from Aβ internalization from the extracellular milieu. We discuss here the different molecular mechanisms that are responsible for Aβ internalization in neurons and the links between Aβ internalization and neuronal dysfunction and death. A brief description of Aβ uptake by glia is also presented.