The neuronal calcium sensor NCS-1 regulates the phosphorylation state and activity of the Gα chaperone and GEF Ric-8A.

The neuronal calcium sensor 1 (NCS-1), an EF-hand Ca2+ binding protein, and Ric-8A coregulate synapse number and probability of neurotransmitter release. Recently, the structures of Ric-8A bound to Gα have revealed how Ric-8A phosphorylation promotes Gα recognition and activity as a chaperone and guanine nucleotide exchange factor. However, the molecular mechanism by which NCS-1 regulates Ric-8A activity and its interaction with Gα subunits is not well understood. Given the interest in the NCS-1/Ric-8A complex as a therapeutic target in nervous system disorders, it is necessary to shed light on this molecular mechanism of action at atomic level. We have reconstituted NCS-1/Ric-8A complexes to conduct a multimodal approach and determine the sequence of Ca2+ signals and phosphorylation events that promote the interaction of Ric-8A with Gα. Our data show that the binding of NCS-1 and Gα to Ric-8A are mutually exclusive. Importantly, NCS-1 induces a structural rearrangement in Ric-8A that traps the protein in a conformational state that is inaccessible to casein kinase II-mediated phosphorylation, demonstrating one aspect of its negative regulation of Ric-8A-mediated G-protein signaling. Functional experiments indicate a loss of Ric-8A guanine nucleotide exchange factor (GEF) activity toward Gα when complexed with NCS-1, and restoration of nucleotide exchange activity upon increasing Ca2+ concentration. Finally, the high-resolution crystallographic data reported here define the NCS-1/Ric-8A interface and will allow the development of therapeutic synapse function regulators with improved activity and selectivity.

Indispensable role of Nectin-like 4 in regulating synapse-related molecules, synaptic structure, and individual behavior.

Nectin-like family members (Necls) are involved in synaptic organization. In contrast to that of Necl-2/CADM1/SynCAM1, which is critical in synaptic events, investigation of Necl-4/CADM4/SynCAM4 in synapses has largely lagged behind given the particularity of homophilic self-interactions compared to interactions with other Necls. We sought to further understand the role of Necl-4 in synapses and found that knockout of Necl-4 led to aberrant expression levels of proteins mediating synaptic function in cortex homogenates and augmented accumulation of ionotropic glutamate receptor in postsynaptic density fractions, although a compensatory effect of Necl-1 on the expression levels existed. Concurrently, we also found increased synaptic clefts in the cortex and simplified dendritic morphology of primary cultured cortical neurons. Experiments on individual behaviors suggested that compared to their wild-type littermates, Necl-4-KO mice exhibited impaired acquisition of spatial memory and working memory and enhanced behavioral despair and anxiety-like behavior. These findings suggest that Necl-4 mediates synaptic function and related behaviors through an indispensable role and offer a new perspective about collaboration and specialization among Necls.

Energy-guided synapse coupling between neurons under noise.

From a physical viewpoint, any external stimuli including noise disturbance can inject energy into the media, and the electric response is regulated by the equivalent electric stimulus. For example, mode transition in electric activities in neurons occurs and kinds of spatial patterns are formed during the wave propagation. In this paper, a feasible criterion is suggested to explain and control the growth of electric synapse and memristive synapse between Hindmarsh-Rose neurons in the presence of noise. It is claimed that synaptic coupling can be enhanced adaptively due to energy diversity, and the coupling intensity is increased to a saturation value until two neurons reach certain energy balance. Two identical neurons can reach perfect synchronization when electric synapse coupling is further increased. This scheme is also considered in a chain neural network and uniform noise is applied on all neurons. However, reaching synchronization becomes difficult for neurons in presenting spiking, bursting, and chaotic and periodic patterns, even when the local energy balance is corrupted to continue further growth of the coupling intensity. In the presence of noise, energy diversity becomes uncertain because of spatial diversity in excitability, and development of regular patterns is blocked. The similar scheme is used to control the growth of memristive synapse for neurons, and the synchronization stability and pattern formation are controlled by the energy diversity among neurons effectively. These results provide possible guidance for knowing the biophysical mechanism for synapse growth and energy flow can be applied to control the synchronous patterns between neurons.

Low-Consumption Synaptic Devices Based on Gate-All-Around InAs Nanowire Field-Effect Transistors.

In this work, an artificial electronic synaptic device based on gate-all-around InAs nanowire field-effect transistor is proposed and analyzed. The deposited oxide layer (In2O3) on the InAs nanowire surface serves as a charge trapping layer for information storage. The gate voltage pulse serves as stimuli of the presynaptic membrane, and the drain current and channel conductance are treated as post-synaptic current and weights of the postsynaptic membrane, respectively. At low gate voltages, the device simulates synaptic behaviors including short-term depression and long-term depression. By increasing the amplitude and quantity of gate voltage pulses, the transition from short-term depression to long-term potentiation can be achieved. The device exhibits a large memory window of over 1 V and a minimal energy consumption of 12.5 pJ per synaptic event. This work may pave the way for the development of miniaturized low-consumption synaptic devices and related neuromorphic systems.

Early-Life Pb Exposure Might Exert Synapse-Toxic Effects Via Inhibiting Synapse-Associated Membrane Protein 2 (VAMP2) Mediated by Upregulation of miR-34b.

BACKGROUND: Early-life Pb exposure can cause behavioral and cognitive problems and induce symptoms of hyperactivity, impulsivity, and inattention in children. Studies showed that blood lead levels were highly correlated with neuropsychiatric disorders, and effects of neurotoxicity might persist and affect the incidence of neurodegenerative diseases, for example Alzheimer's disease (AD). OBJECTIVE: To explore possible mechanisms of developmental Pb-induced neuropsychiatric dysfunctions. METHODS: Children were divided into low blood lead level (BLL) group (0-50.00µg/L) and high BLL group (> 50.00µg/L) and blood samples were collected. miRNA array was used to testify miRNA expression landscape between two groups. Correlation analysis and real-time PCR were applied to find miRNAs that altered in Pb and neuropsychiatric diseases. Animal models and cell experiments were used to confirm the effect of miRNAs in response to Pb, and siRNA and luciferase experiments were conducted to examine their effect on neural functions. RESULTS: miRNA array data and correlation analysis showed that miR-34b was the most relevant miRNA among Pb neurotoxicity and neuropsychiatric disorders, and synapse-associated membrane protein 2 (VAMP2) was the target gene regulating synapse function. In vivo and in vitro studies showed Pb exposure injured rats' cognitive abilities and induced upregulation of miR-34b and downregulation of VAMP2, resulting in decreases of hippocampal synaptic vesicles. Blockage of miR-34b mitigated Pb's effects on VAMP2 in vitro. CONCLUSION: Early-life Pb exposure might exert synapse-toxic effects via inhibiting VAMP2 mediated by upregulation of miR-34b and shed a light on the underlying relationship between Pb neurotoxicity and developmental neuropsychiatric disorders.

Overexpression of Tropomyosin Isoform Tpm3.1 Does Not Alter Synaptic Function in Hippocampal Neurons.

Tropomyosin (Tpm) has been regarded as the master regulator of actin dynamics. Tpms regulate the binding of the various proteins involved in restructuring actin. The actin cytoskeleton is the predominant cytoskeletal structure in dendritic spines. Its regulation is critical for spine formation and long-term activity-dependent changes in synaptic strength. The Tpm isoform Tpm3.1 is enriched in dendritic spines, but its role in regulating the synapse structure and function is not known. To determine the role of Tpm3.1, we studied the synapse structure and function of cultured hippocampal neurons from transgenic mice overexpressing Tpm3.1. We recorded hippocampal field excitatory postsynaptic potentials (fEPSPs) from brain slices to examine if Tpm3.1 overexpression alters long-term synaptic plasticity. Tpm3.1-overexpressing cultured neurons did not show a significantly altered dendritic spine morphology or synaptic activity. Similarly, we did not observe altered synaptic transmission or plasticity in brain slices. Furthermore, expression of Tpm3.1 at the postsynaptic compartment does not increase the local F-actin levels. The results suggest that although Tpm3.1 localises to dendritic spines in cultured hippocampal neurons, it does not have any apparent impact on dendritic spine morphology or function. This is contrary to the functional role of Tpm3.1 previously observed at the tip of growing neurites, where it increases the F-actin levels and impacts growth cone dynamics.

Deletion of ß-Neurexins in Mice Alters the Distribution of Dense-Core Vesicles in Presynapses of Hippocampal and Cerebellar Neurons.

Communication between neurons through synapses includes the release of neurotransmitter-containing synaptic vesicles (SVs) and of neuromodulator-containing dense-core vesicles (DCVs). Neurexins (Nrxns), a polymorphic family of cell surface molecules encoded by three genes in vertebrates (Nrxn1-3), have been proposed as essential presynaptic organizers and as candidates for cell type-specific or even synapse-specific regulation of synaptic vesicle exocytosis. However, it remains unknown whether Nrxns also regulate DCVs. Here, we report that at least ß-neurexins (ß-Nrxns), an extracellularly smaller Nrxn variant, are involved in the distribution of presynaptic DCVs. We found that conditional deletion of all three ß-Nrxn isoforms in mice by lentivirus-mediated Cre recombinase expression in primary hippocampal neurons reduces the number of ultrastructurally identified DCVs in presynaptic boutons. Consistently, colabeling against marker proteins revealed a diminished population of chromogranin A- (ChrgA-) positive DCVs in synapses and axons of ß-Nrxn-deficient neurons. Moreover, we validated the impaired DCV distribution in cerebellar brain tissue from constitutive ß-Nrxn knockout (ß-TKO) mice, where DCVs are normally abundant and ß-Nrxn isoforms are prominently expressed. Finally, we observed that the ultrastructure and marker proteins of the Golgi apparatus, responsible for packaging neuropeptides into DCVs, seem unchanged. In conclusion, based on the validation from the two deletion strategies in conditional and constitutive KO mice, two neuronal populations from the hippocampus and cerebellum, and two experimental protocols in cultured neurons and in the brain tissue, this study presented morphological evidence that the number of DCVs at synapses is altered in the absence of ß-Nrxns. Our results therefore point to an unexpected contribution of ß-Nrxns to the organization of neuropeptide and neuromodulator function, in addition to their more established role in synaptic vesicle release.

Ubiquitin and Ubiquitin-Like Proteins in the Critical Equilibrium between Synapse Physiology and Intellectual Disability.

Posttranslational modifications (PTMs) represent a dynamic regulatory system that precisely modulates the functional organization of synapses. PTMs consist in target modifications by small chemical moieties or conjugation of lipids, sugars or polypeptides. Among them, ubiquitin and a large family of ubiquitin-like proteins (UBLs) share several features such as the structure of the small protein modifiers, the enzymatic cascades mediating the conjugation process, and the targeted aminoacidic residue. In the brain, ubiquitination and two UBLs, namely sumoylation and the recently discovered neddylation orchestrate fundamental processes including synapse formation, maturation and plasticity, and their alteration is thought to contribute to the development of neurological disorders. Remarkably, emerging evidence suggests that these pathways tightly interplay to modulate the function of several proteins that possess pivotal roles for brain homeostasis as well as failure of this crosstalk seems to be implicated in the development of brain pathologies. In this review, we outline the role of ubiquitination, sumoylation, neddylation, and their functional interplay in synapse physiology and discuss their implication in the molecular pathogenesis of intellectual disability (ID), a neurodevelopmental disorder that is frequently comorbid with a wide spectrum of brain pathologies. Finally, we propose a few outlooks that might contribute to better understand the complexity of these regulatory systems in regard to neuronal circuit pathophysiology.

Long noncoding RNA GM12371 acts as a transcriptional regulator of synapse function.

Despite the growing evidence suggesting that long noncoding RNAs (lncRNAs) are critical regulators of several biological processes, their functions in the nervous system remain elusive. We have identified an lncRNA, GM12371, in hippocampal neurons that is enriched in the nucleus and necessary for synaptic communication, synapse density, synapse morphology, and dendritic tree complexity. Mechanistically, GM12371 regulates the expression of several genes involved in neuronal development and differentiation, as well as expression of specific lncRNAs and their cognate mRNA targets. Furthermore, we find that cAMP-PKA signaling up-regulates the expression of GM12371 and that its expression is essential for the activity-dependent changes in synaptic transmission in hippocampal neurons. Taken together, our data establish a key role for GM12371 in regulating synapse function.

Noelin1 Affects Lateral Mobility of Synaptic AMPA Receptors.

Lateral diffusion on the neuronal plasma membrane of the AMPA-type glutamate receptor (AMPAR) serves an important role in synaptic plasticity. We investigated the role of the secreted glycoprotein Noelin1 (Olfactomedin-1 or Pancortin) in AMPAR lateral mobility and its dependence on the extracellular matrix (ECM). We found that Noelin1 interacts with the AMPAR with high affinity, however, without affecting rise- and decay time and desensitization properties. Noelin1 co-localizes with synaptic and extra-synaptic AMPARs and is expressed at synapses in an activity-dependent manner. Single-particle tracking shows that Noelin1 reduces lateral mobility of both synaptic and extra-synaptic GluA1-containing receptors and affects short-term plasticity. While the ECM does not constrain the synaptic pool of AMPARs and acts only extrasynaptically, Noelin1 contributes to synaptic potentiation by limiting AMPAR mobility at synaptic sites. This is the first evidence for the role of a secreted AMPAR-interacting protein on mobility of GluA1-containing receptors and synaptic plasticity.

Identification of an acute functional cross-talk between amyloid-ß and glucocorticoid receptors at hippocampal excitatory synapses.

Amyloid-ß is a peptide released by synapses in physiological conditions and its pathological accumulation in brain structures necessary for memory processing represents a key toxic hallmark underlying Alzheimer's disease. The oligomeric form of Amyloid-ß (Aßο) is now believed to represent the main Amyloid-ß species affecting synapse function. Yet, the exact molecular mechanism by which Aßο modifies synapse function remains to be fully elucidated. There is accumulating evidence that glucocorticoid receptors (GRs) might participate in Aßο generation and activity in the brain. Here, we provide evidence for an acute functional cross-talk between Aß and GRs at hippocampal excitatory synapses. Using live imaging and biochemical analysis of post-synaptic densities (PSD) in cultured hippocampal neurons, we show that synthetic Aßo (100 nM) increases GR levels in spines and PSD. Also, in these cultured neurons, blocking GRs with two different GR antagonists prevents Aßo-mediated PSD95 increase within the PSD. By analyzing long-term potentiation (LTP) and long-term depression (LTD) in ex vivo hippocampal slices after pharmacologically blocking GR, we also show that GR signaling is necessary for Aßo-mediated LTP impairment, but not Aßo-mediated LTD induction. The necessity of neuronal GRs for Aßo-mediated LTP was confirmed by genetically removing GRs in vivo from CA1 neurons using conditional GR mutant mice. These results indicate a tight functional interplay between GR and Aß activities at excitatory synapses.

Mystery Neurotransmitters! An Active Learning Activity on Synaptic Function for Undergraduate Students.

A core learning objective of undergraduate neuroscience education is an understanding of synaptic function and neurotransmission. This article presents a critical thinking activity in which students explore and evaluate neurotransmitter function at the synapse. Students analyze fictional datasets to identify fundamental processes involved in synaptic function, first following evoked neurotransmitter release and then in response to two "mystery" drugs. The activity requires students to synthesize information from multiple datasets in order to interpret data and figures, skills crucial to science literacy. Students' self-reported perceptions and declarative knowledge following the activity suggest that this activity promoted critical thinking and deep learning related to synaptic function. The activity is amenable to collaborative, team-based learning and can be modified for a range of undergraduate courses in neuroscience, psychology and biology.

The Structure of the Synaptic Vesicle-Plasma Membrane Interface Constrains SNARE Models of Rapid, Synchronous Exocytosis at Nerve Terminals.

Contemporary models of neurotransmitter release invoke direct or indirect interactions between the Ca2+ sensor, synaptotagmin and the incompletely zippered soluble, N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) complex. However, recent electron microscopic (EM) investigations have raised pragmatic issues concerning the mechanism by which SNAREs trigger membrane fusion at nerve terminals. The first issue is related to the finding that the area of contact between a "fully primed" synaptic vesicle and the plasma membrane can exceed 600 nm2. Approximately four-thousands lipid molecules can inhabit this contact zone. Thus, renewed efforts will be needed to explain how the zippering of as few as two SNARE complexes mobilizes these lipids to achieve membrane fusion. The second issue emerges from the finding that "docking filaments" are sandwiched within the area of vesicle-plasma membrane contact. It is challenging to reconcile the location of these filaments with SNARE models of exocytosis. Instead, this commentary outlines how these data are more compatible with a model in which a cluster of synaptotagmins catalyzes exocytotic membrane fusion.

Gene Function Prediction Based on Developmental Transcriptomes of the Two Sexes in C. elegans.

We compare whole-animal RNA-seq transcriptomes for C. elegans males and hermaphrodites from the late L3 larval stage to young adulthood. During this interval, male sexual structures develop, including extensive neurogenesis and synaptogenesis that nearly doubles the size of the nervous system. Previous genome-wide expression studies in C. elegans have usually focused on only one sex-the hermaphrodite-and there are a relatively large number of genes that remain without meaningful annotation. In the present study, differential expression analysis of the RNA-seq data revealed 1,751 genes expressed at a higher level in the male. By differential expression and co-expression analyses, we identified transcription factors required for differentiation of male genital structures, semen proteins, and candidates for components of synapse function. Comparison with other prediction tools suggests that our dataset can expand gene predictions. The results validate the dataset as a rich resource for future gene discovery in C. elegans.

Regulated Dynamic Trafficking of Neurexins Inside and Outside of Synaptic Terminals.

Synapses depend on trafficking of key membrane proteins by lateral diffusion from surface populations and by exocytosis from intracellular pools. The cell adhesion molecule neurexin (Nrxn) plays essential roles in synapses, but the dynamics and regulation of its trafficking are unknown. Here, we performed single-particle tracking and live imaging of transfected, epitope-tagged Nrxn variants in cultured rat and mouse wild-type or knock-out neurons. We observed that structurally larger αNrxn molecules are more mobile in the plasma membrane than smaller ßNrxns because αNrxns displayed higher diffusion coefficients in extrasynaptic regions and excitatory or inhibitory terminals. We found that well characterized interactions with extracellular binding partners regulate the surface mobility of Nrxns. Binding to neurexophilin-1 (Nxph1) reduced the surface diffusion of αNrxns when both molecules were coexpressed. Conversely, impeding other interactions by insertion of splice sequence #4 or removal of extracellular Ca(2+) augmented the mobility of αNrxns and ßNrxns. We also determined that fast axonal transport delivers Nrxns to the neuronal surface because Nrxns comigrate as cargo on synaptic vesicle protein transport vesicles (STVs). Unlike surface mobility, intracellular transport of ßNrxn(+) STVs was faster than that of αNrxns, but both depended on the microtubule motor protein KIF1A and neuronal activity regulated the velocity. Large spontaneous fusion of Nrxn(+) STVs occurred simultaneously with synaptophysin on axonal membranes mostly outside of active presynaptic terminals. Surface Nrxns enriched at synaptic terminals where αNrxns and Nxph1/αNrxns recruited GABAAR subunits. Therefore, our results identify regulated dynamic trafficking as an important property of Nrxns that corroborates their function at synapses. SIGNIFICANCE STATEMENT: Synapses mediate most functions in our brains and depend on the precise and timely delivery of key molecules throughout life. Neurexins (Nrxns) are essential synaptic cell adhesion molecules that are involved in synaptic transmission and differentiation of synaptic contacts. In addition, Nrxns have been linked to neuropsychiatric diseases such as autism. Because little is known about the dynamic aspects of trafficking of neurexins to synapses, we investigated this important question using single-molecule tracking and time-lapse imaging. We identify distinct differences between major Nrxn variants both in surface mobility and during intracellular transport. Because their dynamic behavior is highly regulated, for example, by different binding activities, these processes have immediate consequences for the function of Nrxns at synapses.

Deletion of KIBRA, protein expressed in kidney and brain, increases filopodial-like long dendritic spines in neocortical and hippocampal neurons in vivo and in vitro.

Spines are small protrusions arising from dendrites that receive most excitatory synaptic input in the brain. Dendritic spines represent dynamic structures that undergo activity-dependent adaptations, for example, during synaptic plasticity. Alterations of spine morphology, changes of spine type ratios or density have consequently been found in paradigms of learning and memory, and accompany many neuropsychiatric disorders. Polymorphisms in the gene encoding KIBRA, a protein present in kidney and brain, are linked to memory performance and cognition in humans and mouse models. Deletion of KIBRA impairs long-term synaptic plasticity and postsynaptic receptor recycling but no information is available on the morphology of dendritic spines in null-mutant mice. Here, we directly examine the role of KIBRA in spinous synapses using knockout mice. Since KIBRA is normally highly expressed in neocortex and hippocampus at juvenile age, we analyze synapse morphology in intact tissue and in neuronal cultures from these brain regions. Quantification of different dendritic spine types in Golgi-impregnated sections and in transfected neurons coherently reveal a robust increase of filopodial-like long protrusions in the absence of KIBRA. While distribution of pre- and postsynaptic marker proteins, overall synapse ultrastructure and density of asymmetric contacts were remarkably normal, electron microscopy additionally uncovered less perforated synapses and spinules in knockout neurons. Thus, our results indicate that KIBRA is involved in the maintenance of normal ratios of spinous synapses, and may thus provide a structural correlate of altered cognitive functions when this memory-associated molecule is mutated.

LGI1: from zebrafish to human epilepsy.

Mutations in the LGI1 gene predispose to autosomal dominant lateral temporal lobe epilepsy, a rare hereditary form with incomplete penetrance and associated with acoustic auras. LGI1 is not a structural component of an ion channel like most epilepsy-related genes, but is a secreted protein. Mutant null mice exhibit early-onset seizures, and electrophysiological analysis shows abnormal synaptic transmission. LGI1 binds to ADAM23 on the presynaptic membrane and ADAM22 on the postsynaptic membrane, further implicating it in regulating the strength of synaptic transmission. Patients with limbic encephalitis show autoantibodies against LGI1 and develop seizures, supporting a role for LGI1 in synapse transmission in the post developmental brain. LGI1, however, also seems to be involved in aspects of neurite development and dendritic pruning, suggesting an additional role in corticogenesis. LGI1 is also involved in cell movement and suppression of dendritic outgrowth in in vitro systems, possibly involving actin cytoskeleton dynamics. Expression patterns in embryonic development correspond to areas of neuronal migration. Loss of LGI1 expression also impacts on myelination of the central and peripheral nervous systems. In zebrafish embryos, knockdown of lgi1a leads to a seizure-like behavior and abnormal brain development, providing a system to study its role in early embryogenesis. Despite being implicated in a role in both synapse transmission and neuronal development, how LGI1 predisposes to epilepsy is still largely unknown. It appears, however, that LGI1 may function differently in a cell context-specific manner, implying a complex involvement in brain development and function that remains to be defined.

Dominance of P/Q-type calcium channels in depolarization-induced presynaptic FM dye release in cultured hippocampal neurons.

Neurotransmitter release probability is related by high power to the local concentration of calcium in presynaptic terminals, which in turn is controlled by voltage-gated calcium channels. P/Q- and N-type channels trigger synaptic transmission in the majority of neurons of the central nervous system. However, whether and under which conditions both channel types act cooperatively or independently is still insufficiently understood. Previous studies suggested either a dominance of N- or P/Q-type channels, or a synergistic action of both channels, depending on the experimental paradigms. Thus, to provide insight into the properties of neurotransmitter release in cultured mouse hippocampal neurons, we used quantitative analysis of FM dye release from presynaptic boutons induced by high potassium membrane depolarization. Increasing extracellular potassium concentrations revealed a sigmoid dependence of FM dye release to the stimulation strength. Individual and combined application of the P/Q- and N-type channel-specific blockers ω-agatoxin-IVA and ω-conotoxin-GVIA, respectively, allowed us to specifically isolate the contribution of both channel types to release triggered with 40 mM KCl. Analysis of the release kinetics and the fractional release amplitude demonstrate that, whereas in only 15% of the synapses release depended exclusively on P/Q-type channels, the majority of synapses (85%) contained both N- and P/Q-type channels. Nevertheless, the kinetics of FM dye release in synapses containing both channel types was determined by the P/Q-type channels. Together, our data suggest a more direct coupling of P/Q-type channels to synaptic release compared to N-type channels, which may explain the high prevalence of neurological P/Q-type channelopathies.

Nutritional approaches in the risk reduction and management of Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous and devastating neurodegenerative disease with increasing socioeconomic burden for society. In the past 30 y, notwithstanding advances in the understanding of the pathogenesis of the disease and consequent development of therapeutic approaches to novel pathogenic targets, no cure has so far emerged. This contribution focuses on recent nutritional approaches in the risk reduction and management of AD with emphasis on factors providing a rationale for nutritional approaches in AD, including compromised nutritional status, altered nutrient uptake and metabolism, and nutrient requirements for synapse formation. Collectively these factors are believed to result in specific nutritional requirement in AD. The chapter also emphasizes investigated nutritional interventions in patients with AD, including studies with single nutrients and with the specific nutrient combination Fortasyn Connect and discusses the current shift of paradigm to intervene in earlier stages of AD, which offers opportunities for investigating nutritional strategies to reduce the risk for disease progression. Fortasyn Connect was designed to enhance synapse formation and function in AD by addressing the putative specific nutritional requirements and contains docosahexaenoic acid, eicosapentaenoic acid, uridine-5'-mono-phosphate, choline, phospholipids, antioxidants, and B vitamins. Two randomized controlled trials (RCTs) with the medical food Souvenaid, containing Fortasyn Connect, showed that this intervention improved memory performance in mild, drug-naïve patients with AD. Electroencephalography outcome in one of these clinical studies suggests that Souvenaid has an effect on brain functional connectivity, which is a derivative of changed synaptic activity. Thus, these studies suggest that nutritional requirements in AD can be successfully addressed and result in improvements in behavioral and neuro-physiological alterations that are characteristic to AD. The recent advance of methodologies and techniques for early diagnosis of AD facilitates the investigation of strategies to reduce the risk for AD progression in the earliest stages of the disease. Nutrition-based approaches deserve further investigation as an integral part of such strategies due to their low risk for side effects and their potential to affect pathological processes of very early AD.