Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the e4 allele are at increased risk of AD compared with those carrying the more common e3 allele, whereas the e2 allele decreases risk. Presence of the APOE e4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.

/pdf/apolipoprotein-e-and-alzheimer-disease-risk-mechanisms-and-3b8rbhoha8.pdf

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

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The Biomarker Guide

For decades, astrocytes have been considered to be non-excitable support cells of the brain. However, this view has changed radically during the past twenty years. The recent recognition that they are organized in separate territories and possess active properties — notably a competence for the regulated release of 'gliotransmitters', including glutamate — has enabled us to develop an understanding of previously unknown functions for astrocytes. Today, astrocytes are seen as local communication elements of the brain that can generate various regulatory signals and bridge structures (from neuronal to vascular) and networks that are otherwise disconnected from each other. Examples of their specific and essential roles in normal physiological processes have begun to accumulate, and the number of diseases known to involve defective astrocytes is increasing.

Astrocytes, from brain glue to communication elements: the revolution continues.

The molecular mechanisms controlling synaptogenesis in the central nervous system (CNS) are poorly understood. Previous reports showed that a glia-derived factor strongly promotes synapse development in cultures of purified CNS neurons. Here, we identify this factor as cholesterol complexed to apolipoprotein E-containing lipoproteins. CNS neurons produce enough cholesterol to survive and grow, but the formation of numerous mature synapses demands additional amounts that must be provided by glia. Thus, the availability of cholesterol appears to limit synapse development. This may explain the delayed onset of CNS synaptogenesis after glia differentiation and neurobehavioral manifestations of defects in cholesterol or lipoprotein homeostasis.

https://science.sciencemag.org/content/sci/294/5545/1354.full.pdf

CNS synaptogenesis promoted by glia-derived cholesterol

http://www2.neuroscience.umn.edu/eanwebsite/PDF%20GJClub/Cell%20120%20421%202005.pdf

Thrombospondins Are Astrocyte-Secreted Proteins that Promote CNS Synaptogenesis

1. To study the effects of glial cells on synapse formation, we established microcultures of purified rat retinal ganglion cells (RGCs) and monitored synapse (autapse) development in single neurones using electrophysiological recordings, FM1-43 labelling and immunocytochemistry. 2. Solitary neurones grew ramifying neurites, but formed only very few and inefficient excitatory autapses, when cultured for up to 2 weeks in defined medium and in the absence of glial cells. 3. Treatment of glia-free microcultures of RGCs with glia-conditioned medium (GCM) increased the number of autapses per neurone by up to 10-fold. This was indicated by a similar increase in the frequency of spontaneous events and the number of FM1-43-labelled functional release sites and of puncta, where pre- and postsynaptic markers colocalized. 4. In addition, GCM treatment enhanced the efficacy of presynaptic transmitter release as indicated by lower failure rates of stimulation-induced excitatory autaptic currents, a 200-fold increase in the frequency of asynchronous release and an accelerated stimulation-induced FM1-43 destaining. Furthermore, GCM induced an increase in the quantal size. 5. GCM affected autaptic activity not immediately, but with a delay of 24 h, and the effects on stimulation-induced autaptic currents occurred before changes in the frequency of spontaneous events indicating an early strengthening of existing autapses followed by a later increase in autapse number. 6. The observed effects were mediated by proteinase K-sensitive factors in GCM and occurred independently of electrical activity. 7. These results suggest that soluble glia-derived signals induce synapse formation and maturation in neurones of the central nervous system (CNS).

Glia‐derived signals induce synapse formation in neurones of the rat central nervous system

Brain development and function relies on the exchange of signals between neurons and glial cells. Here we review a series of recent studies on cultures of purified retinal ganglion cells (RGCs) that point to a new role of glial cells in the formation and plasticity of synaptic connections. The results suggest that neurons must import glia-derived cholesterol via lipoproteins to form numerous and efficient synaptic connections. This finding may explain why throughout the central nervous system (CNS) the main phase of synaptogenesis starts synchronously after glia differentiation and why astrocytes produce apolipoprotein E (apoE) and cholesterol-containing lipoproteins. Experimental tests of these hypotheses may further our understanding of the cholesterol metabolism in the brain and may help to explain neurologic symptoms resulting from defective cholesterol and lipoprotein metabolism.

Role of glia-derived cholesterol in synaptogenesis: new revelations in the synapse-glia affair.

The primary olfactory neuropil, the antennal lobe (AL) in insects, is organized in glomeruli. Glomerular activity patterns are believed to represent the across-fibre pattern of the olfactory code. These patterns depend on an organized innervation from the afferent receptor cells, and interconnections of local interneurons. It is unclear how the complex organization of the AL is achieved ontogenetically. In this study, we measured the functional activity patterns elicited by stimulation with odours in the right and the left AL of the same honeybee (Apis mellifera) using optical imaging of the calcium-sensitive dye calcium green. We show here that these patterns are bilaterally symmetrical (n 5 25 bees). This symmetry holds true for all odours tested, irrespective of their role as pheromones or as environmental odours, or whether they were pure substances or complex blends (n 5 13 odours). Therefore, we exclude that activity dependent mechanisms local to one AL determine the functional glomerular activity. This identity is genetically predetermined. Alternatively, if activity dependent processes are involved, bilateral connections would have to shape symmetry, or, temporal constraints could lead to identical patterns on both sides due to their common history of odour exposure.

/pdf/odour-coding-is-bilaterally-symmetrical-in-the-antennal-nsks2p3oak.pdf

Odour coding is bilaterally symmetrical in the antennal lobes of honeybees (Apis mellifera)

There is increasing evidence that synapse function depends on interactions with glial cells, namely astrocytes Studies on specific neurons of the central nervous system (CNS) indicated that glial signals also control synapse development, but it remained unclear whether this is a general principle that applies to other neuronal cell types To address this question, we developed new methods to immunoisolate neurons from different brain regions of postnatal mice and to culture them in a chemically defined medium Electrophysiological recordings and immunocytochemical staining revealed vigorous synaptogenesis in hippocampal and cerebellar neurons, but not in retinal ganglion cells (RGCs) in the absence of glial cells Co-culture with glia promoted synapse formation in RGCs as indicated by a strong increase in the incidence and frequency of action potential-independent miniature synaptic currents, but showed no such effects in hippocampal or cerebellar neurons On the other hand, glial signals promoted the efficacy of excitatory synapses in all regions as indicated by an increase in the size of spontaneous synaptic events in cerebellar cultures and of miniature synaptic currents in hippocampal neurons and RGCs Inhibitory synaptic currents remained largely unaffected by glia Our results indicate that in the mammalian CNS, the way that glial signals promote the development of excitatory synapses depends on the type of neuron

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2006.117358

Karl Nägler

Papers

CNS synaptogenesis promoted by glia-derived cholesterol

Glia‐derived signals induce synapse formation in neurones of the rat central nervous system

Role of glia-derived cholesterol in synaptogenesis: new revelations in the synapse-glia affair.

Odour coding is bilaterally symmetrical in the antennal lobes of honeybees (Apis mellifera)

Regional variations in the glial influence on synapse development in the mouse CNS