Neurite Outgrowth Activity Research Articles

Expanded ATXN1 alters transcription and calcium signaling in SCA1 human motor neurons differentiated from induced pluripotent stem cells

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited and lethal neurodegenerative disease caused by the abnormal expansion of CAG repeats in the ATAXIN-1 (ATXN1) gene. Pathological studies identified dysfunction and loss of motor neurons (MNs) in the brain stem and spinal cord, which are thought to contribute to premature lethality by affecting the swallowing and breathing of SCA1 patients. However, the molecular and cellular mechanisms of MN pathogenesis remain unknown.To study SCA1 pathogenesis in human MNs, we differentiated induced pluripotent stem cells (iPSCs) derived from SCA1 patients and their unaffected siblings into MNs. We examined proliferation of progenitor cells, neurite outgrowth, spontaneous and glutamate-induced calcium activity of SCA1 MNs to investigate cellular mechanisms of pathogenesis. RNA sequencing was then used to identify transcriptional alterations in iPSC-derived MN progenitors (pMNs) and MNs which could underlie functional changes in SCA1 MNs. We found significantly decreased spontaneous and evoked calcium activity and identified dysregulation of genes regulating calcium signaling in SCA1 MNs. These results indicate that expanded ATXN1 causes dysfunctional calcium signaling in human MNs.

Tumor-associated genetic amplifications impact extracellular vesicle miRNA cargo and their recruitment of nerves in head and neck cancer.

Cancer neuroscience is an emerging field of cancer biology focused on defining the interactions and relationships between the nervous system, developing malignancies, and their environments. Our previous work demonstrates that small extracellular vesicles (sEVs) released by head and neck squamous cell carcinomas (HNSCCs) recruit loco-regional nerves to the tumor. sEVs contain a diverse collection of biological cargo, including microRNAs (miRNAs). Here, we asked whether two genes commonly amplified in HNSCC, CCND1, and PIK3CA, impact the sEV miRNA cargo and, subsequently, sEV-mediated tumor innervation. To test this, we individually overexpressed these genes in a syngeneic murine HNSCC cell line, purified their sEVs, and tested their neurite outgrowth activity on dorsal root ganglia (DRG) neurons invitro. sEVs purified from Ccnd1-overexpressing cells significantly increased neurite outgrowth of DRG compared to sEVs from parental or Pik3ca over-expressing cells. When implanted into C57BL/6 mice, Ccnd1 over-expressing tumor cells promoted significantly more tumor innervation invivo. qPCR analysis of sEVs shows that increased expression of Ccnd1 altered the packaging of miRNAs (miR-15-5p, miR-17-5p, and miR-21-5p), many of which target transcripts important in regulating axonogenesis. These data indicate that genetic amplifications harbored by malignancies impose changes in sEV miRNA cargo, which can influence tumorc innervation.

Assessment of the Developmental Neurotoxicity of Environmental Chemicals: Investigating the Mechanisms & Identifying Potential Biomarkers

Background: Developmental neurotoxicity resulting from exposure to environmental chemicals is a significant public health concern. Understanding the mechanisms underlying such neurotoxicity and identifying potential biomarkers are essential for early detection and effective risk assessment. Objective: This study aimed to assess the developmental neurotoxicity of selected environmental chemicals and investigate the underlying mechanisms. Additionally, the study sought to identify potential biomarkers for early detection and monitoring of developmental neurotoxicity. Methods: In vitro neurodevelopmental models were established, including neuronal cell cultures and organoid systems, to evaluate the neurotoxic effects of environmental chemicals. Key endpoints, such as neuronal viability, morphology, neurite outgrowth, synaptogenesis, and synaptic activity, were assessed using appropriate assays and imaging techniques. Mechanistic investigations involved exploring oxidative stress, inflammation, disruption of neurotransmitter systems, and interference with neurodevelopmental processes through gene expression analysis, protein profiling, and signaling pathway investigations. Results: Exposure of the in vitro models to selected environmental chemicals resulted in significant neurotoxic effects, including impaired neuronal viability, disrupted morphological development, and altered synaptic activity. Mechanistic investigations revealed the involvement of oxidative stress and disruption of neurotransmitter systems in the observed neurotoxicity. Furthermore, several potential biomarkers, including gene expression changes and epigenetic modifications, showed significant correlations with developmental neurotoxicity. Conclusion: This study demonstrates the developmental neurotoxicity of environmental chemicals in in vitro neurodevelopmental models. The findings highlight the role of oxidative stress and neurotransmitter disruption as key mechanisms underlying neurotoxic effects. Moreover, the identification of potential biomarkers provides promising avenues for early detection and monitoring of developmental neurotoxicity. These results contribute to a better understanding of the risks associated with environmental chemical exposure during neurodevelopment and have implications for risk assessment and regulatory guidelines.

Neuroprotective Activity of Catharanthus roseus Ethanol Extract by Acetylcholinesterase Inhibition and Neurite Outgrowth Studies

Aims: To investigate biological activities for neuroprotective effect of Catharanthus roseus.
 Methodology: Catharanthus roseus was identified using DNA barcoding, utilizing matK, trnH-psbA, and rbcL markers. Additionally, thin-layer chromatography (TLC) method was used to analyze the phytochemistry compounds present in the C. roseus extracts. Moreover, acetylcholinesterase (AChE) inhibition activity was tested using a modified Ellman’s method. Finally, neurite outgrowth activity was determined in rat glial C6 cells treated with varying concentrations of C. roseus extracts.
 Results: Overall, the plant samples which were collected in Laocai, Vietnam were successfully identified through DNA barcoding regions, using trnH-psbA, matK, and rbcL genes. Phytochemical analysis detected the presence of sterols, terpenoids, flavonoids, polyphenolic in the ethanol extract and its fraction from C. roseus. Additionally, the extracts of C. roseus displayed remarkably high acetylcholinesterase inhibitory activity. Moreover, the ethanol extract of C. roseus shown the most potent neurotrophic activity in a preliminary cell-based screening based on C6 cells neurite outgrowth.
 Conclusion: These results demonstrate that Catharanthus roseus could be a strong candidate for developing pharmacological drugs to treat neurodegenerative diseases.

Proteasomal Stimulation by MK886 and Its Derivatives Can Rescue Tau-Induced Neurite Pathology.

Proteasomal degradation of intrinsically disordered proteins, such as tau, is a critical component of proteostasis in both aging and neurodegenerative diseases. In this study, we investigated proteasomal activation by MK886 (MK). We previously identified MK as a lead compound capable of modulating tau oligomerization in a cellular FRET assay and rescuing P301L tau-induced cytotoxicity. We first confirmed robust proteasomal activation by MK using 20S proteasomal assays and a cellular proteasomal tau-GFP cleavage assay. We then show that MK treatment can significantly rescue tau-induced neurite pathology in differentiated SHSY5Y neurospheres. Due to this compelling result, we designed a series of seven MK analogs to determine if proteasomal activity is sensitive to structural permutations. Using the proteasome as the primary MOA, we examined tau aggregation, neurite outgrowth, inflammation, and autophagy assays to identify two essential substituents of MK that are required for compound activity: (1) removal of the N-chlorobenzyl group from MK negated both proteasomal and autophagic activity and reduced neurite outgrowth; and (2) removal of the indole-5-isopropyl group significantly improved neurite outgrowth and autophagy activity but reduced its anti-inflammatory capacity. Overall, our results suggest that the combination of proteasomal/autophagic stimulation and anti-inflammatory properties of MK and its derivatives can decrease tau-tau interactions and help rebalance dysfunctional proteostasis. Further development of MK to optimize its proteasomal, autophagic, and anti-inflammatory targets may lead to a novel therapeutic that would be beneficial in aging and neurodegenerative diseases.

Total Synthesis of Illisimonin A and Merrilactone A

AbstractIllicium sesquiterpenes are a large family of biologically active secondary metabolites isolated from Illicium species of plants and are well‐known for their activity of neurite outgrowth in cultured neurons. Herein, we propose a comprehensive biosynthetic pathway for illicium sesquiterpenes and report a synthetic route to illisimonin A and merrilactone A based on it. We think that the carbon scaffolds of most of the illicium sesquiterpenes could be synthesized from a dicarbonyl derivative of allo‐cedrane through retro‐Dieckmann condensation, oxidative cleavage and aldol reaction at suitable oxidation states in Nature. The common intermediate for illisimonin A and merrilactone A similar to the dicarbonyl derivative of allo‐cedrane was assembled with up to 82 % ee by an asymmetric intramolecular desymmetrizing reductive Heck reaction by the use of a new type of chiral phosphine ligand. The syntheses of illisimonin A and merrilactone A supported the key transformations of the proposed biosynthetic pathway.

Total Synthesis of Illisimonin A and Merrilactone A.

Illicium sesquiterpenes are a large family of biologically active secondary metabolites isolated from Illicium species of plants and are well-known for their activity of neurite outgrowth in cultured neurons. Herein, we propose a comprehensive biosynthetic pathway for illicium sesquiterpenes and report a synthetic route to illisimonin A and merrilactone A based on it. We think that the carbon scaffolds of most of the illicium sesquiterpenes could be synthesized from a dicarbonyl derivative of allo-cedrane through retro-Dieckmann condensation, oxidative cleavage and aldol reaction at suitable oxidation states in Nature. The common intermediate for illisimonin A and merrilactone A similar to the dicarbonyl derivative of allo-cedrane was assembled with up to 82 % ee by an asymmetric intramolecular desymmetrizing reductive Heck reaction by the use of a new type of chiral phosphine ligand. The syntheses of illisimonin A and merrilactone A supported the key transformations of the proposed biosynthetic pathway.

In vivo Acetylcholinesterase activity and Antioxidant property of Cucurbita pepo ethanolic extract in Alzheimer’s disease induced by Aluminium chloride in Sprague Dawley rat model

The pathophysiology of Alzheimer's disease (AD) typically begins before symptoms manifest. Early diagnosis and treatment can slow down the disease progression and improve the prognosis. Decreased acetylcholine, antioxidants, and polyunsaturated fatty acids enhance the progression of AD. Phytochemicals present in the Cucurbita pepo (C. pepo) plants may have anti-cholinesterase activity. Therefore, this study was performed using ethanolic extract of pumpkin seeds in the AlCl3 induced AD in Sprague Dawley rats. These rats were categorized into five groups, i.e., control, disease control (AlCl3), standard (Rivastigmine), and two treatment groups, one with 100mg/kg and the other with 200mg/kg of the pumpkin seed extract which was given once daily orally for 28days. The rats were assessed for behavioral and biochemical parameters such as antioxidant enzymes and acetyl-cholinesterase levels in brain homogenate. There was statistically significant (p<0.005) improvement in behavioral parameters and increase antioxidant levels and decrease acetylcholinesterase levels in the seed extract treatment groups compared to the AD rats. GC-MS analysis of C.pepo seeds showed the presence of polyunsaturated fatty acids, which have a significant role in neurite outgrowth activity. To conclude, the 80% ethanolic extract of Cucurbita pepo (pumpkin seeds) has anticholinesterase, antioxidant, and anti-inflammatory activity and can prevent memory impairment.

Metabolic contributions to neuronal deficits caused by genomic disruption of schizophrenia risk gene SETD1A

Regulation of neuronal metabolism during early brain development is crucial for directing synaptic plasticity and proper circuit formation. Alterations in neuronal glycolysis or mitochondrial function are associated with several neuropsychiatric disorders, including schizophrenia. Recently, loss-of-function mutations in SETD1A, a histone methyltransferase, have been linked to increased schizophrenia risk and global developmental delay. Here, we show that heterozygous disruption of SETD1A in human induced pluripotent stem cell (hiPSC)-derived neurons results in reduced neurite outgrowth and spontaneous activity, two phenotypes commonly associated with schizophrenia, as well as alterations in metabolic capacity. Furthermore, supplementing culture media with metabolic intermediates ameliorated changes in neurite outgrowth and spontaneous activity, suggesting that metabolic dysfunction contributes to neuronal phenotypes caused by SETD1A haploinsufficiency. These findings highlight a previously unknown connection between SETD1A function, metabolic regulation, and neuron development, and identifies alternative avenues for therapeutic development.

Neurotrophic and Immunomodulatory Lanostane Triterpenoids from Wood-Inhabiting Basidiomycota.

Neurotrophins such as nerve growth factor (ngf) and brain-derived neurotrophic factor (bdnf) play important roles in the central nervous system. They are potential therapeutic drugs for the treatment of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. In this study, we investigated the neurotrophic properties of triterpenes isolated from fruiting bodies of Laetiporus sulphureus and a mycelial culture of Antrodia sp. MUCL 56049. The structures of the isolated compounds were elucidated based on nuclear magnetic resonance (NMR) spectroscopy in combination with high-resolution electrospray mass spectrometry (HR-ESIMS). The secondary metabolites were tested for neurotrophin (ngf and bdnf) expression levels on human astrocytoma 1321N1 cells. Neurite outgrowth activity using rat pheochromocytoma (PC-12) cells was also determined. Twelve triterpenoids were isolated, of which several potently stimulated the expression of neurotrophic factors, namely, ngf (sulphurenic acid, 15α-dehydroxytrametenolic acid, fomefficinic acid D, and 16α-hydroxyeburicoic acid) and bdnf (sulphurenic acid and 15α-dehydroxytrametenolic acid), respectively. The triterpenes also potentiated ngf-induced neurite outgrowth in PC-12 cells. This is, to the best of our knowledge, the first report on the compound class of lanostanes in direct relation to bdnf and ngf enhancement. These compounds are widespread in medicinal mushrooms; hence, they appear promising as a starting point for the development of drugs and mycopharmaceuticals to combat neurodegenerative diseases. Interestingly, they do not show any pronounced cytotoxicity and may, therefore, be better suited for therapy than many other neurotrophic compounds that were previously reported.

Design, synthesis and neurite outgrowth activity of novel ganglioside GM1 derivatives by remodeling of the fatty acid moiety

Ganglioside GM1 is a glycosphingolipid found on mammalian cell membranes, and it is involved in ischemic encephalopathy, spinal cord injury and neurodegenerative diseases. Fatty acids, as a structure module of GM1, have been reported to affect its physiological function and neurite growth activity. Due to the limitation of preparation methods, the function of GM1 derivatives containing different fatty acids in nerve cells has not been systematically studied. To discover novel GM1 derivatives as nerve growth-promoting agents, we developed an efficient SA_SCDase enzymatic synthetic system of GM1 derivatives, yielding twenty GM1 derivatives with unsaturated fatty acid chains in high total yields (16–67%). Subsequently, the neurite outgrowth activities of GM1 derivatives were assessed on Neuro2a Cells. Among all the GM1 derivatives, GM1 (d18:1/C16:1) induced demonstrably neurite outgrowth activity. The subsequent RNA-sequencing (RNA-seq) and Western blot analysis was then performed and indicated that the mechanism of nerve cells growth involved cholesterol biosynthesis regulation by up-regulating SREBP2 expression or ERBB4 phosphorylation to activate the PI3K-mTOR pathway.

The role of NAD metabolism in neuronal differentiation

BackgroundNicotinamide adenine dinucleotide (NAD) metabolism is involved in redox and non-redox reactions that regulate several processes including differentiation of cells of different origins. Here, the role of NAD metabolism in neuronal differentiation, which remains elusive so far, was investigated. Material and methodsA protein-protein interaction network between neurotrophin signaling and NAD metabolic pathways was built. Expression of NAD biosynthetic enzymes in SH-SY5Y cells during retinoic acid (RA)/brain derived neurotrophic factor (BDNF) differentiation, was evaluated. The effects of NAD biosynthetic enzymes QPRT and NAPRT inhibition in neurite outgrowth, cell viability, NAD availability and histone deacetylase (HDAC) activity, were analyzed in RA- and BDNF-differentiated cells. ResultsBioinformatics analysis revealed the interaction between NAD biosynthetic enzyme NMNAT1 and NTRK2, a receptor activated by RA/BDNF sequential treatment. Differences were found in the expression of NAD biosynthetic enzymes during neuronal differentiation, namely, increased QPRT gene expression along the course of RA/BDNF treatment and NAPRT protein expression after a 5-day treatment with RA. QPRT inhibition in BDNF-differentiated SH-SY5Y cells resulted in less neuritic length per cell, decreased expression of the neuronal marker β-III Tubulin and also decreased NAD+ levels and HDAC activity. NAPRT inhibition had no effect in neuritic length per cell, NAD+ levels and HDAC activity. Of note, NAD supplementation along with RA, but not with BDNF, resulted in considerable cell death. ConclusionsTaken together, our results show the involvement of NAD metabolism in neuronal differentiation, specifically, the importance of QPRT-mediated NAD biosynthesis in BDNF-associated SH-SY5Y differentiation and suggest additional roles for NAPRT beyond NAD production in RA-differentiated cells.

Slitrk2 deficiency causes hyperactivity with altered vestibular function and serotonergic dysregulation

SummarySLITRK2 encodes a transmembrane protein that modulates neurite outgrowth and synaptic activities and is implicated in bipolar disorder. Here, we addressed its physiological roles in mice. In the brain, the Slitrk2 protein was strongly detected in the hippocampus, vestibulocerebellum, and precerebellar nuclei—the vestibular-cerebellar-brainstem neural network including pontine gray and tegmental reticular nucleus. Slitrk2 knockout (KO) mice exhibited increased locomotor activity in novel environments, antidepressant-like behaviors, enhanced vestibular function, and increased plasticity at mossy fiber–CA3 synapses with reduced sensitivity to serotonin. A serotonin metabolite was increased in the hippocampus and amygdala, and serotonergic neurons in the raphe nuclei were decreased in Slitrk2 KO mice. When KO mice were treated with methylphenidate, lithium, or fluoxetine, the mood stabilizer lithium showed a genotype-dependent effect. Taken together, Slitrk2 deficiency causes aberrant neural network activity, synaptic integrity, vestibular function, and serotonergic function, providing molecular-neurophysiological insight into the brain dysregulation in bipolar disorders.

Sirtuin inhibition and neurite outgrowth effect as new biological activities for Areca catechu nut alkaloids

BackgroundAreca catechu is distributed in Southeast Asia, and its nut is called “Binrouji” in Japanese. A. nut contains alkaloids typified by arecoline (1), which are reported to exhibit nicotine-like activities such as parasympathetic nerve excitatory activity. A. nut alkaloids, 1, arecaidine (2), guvacoline (3) and guvacine (4), have a basic skeleton similar to nicotinamide (5) which inhibits nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases [sirtuins (SIRTs)], epigenetic enzymes involved in an acquired gene modification. We therefore hypothesized that the A. nut alkaloids might have an inhibitory activity against SIRTs as does nicotinamide (5). PurposeThe present study aimed to examine the potency of these alkaloids as SIRT inhibitors by the methods involving the assays of enzymatic inhibition, cellular acetylated lysine (Ac-Lys) accumulation, chemical pull-down and Western blot, as well as the test of neurite outgrowth. MethodsInhibitory activity of the A. nut alkaloids against SIRT1–3 was measured utilizing the fluorometric SIRT1, 2, or 3 deacetylase assay. Pull down of SIRT1 from the lysate of the neuron-like cell, Neuro 2a, was conducted using arecaidine (2) immobilized with magnetic FG-NH2 beads as bait. The effect of arecoline (1) on the accumulation of acetylated histone was evaluated using an anti-Ac-Lys-antibody. The neurite outgrowth activity of arecoline (1) was assessed by using microscope. ResultsArecoline (1) and arecaidine (2) showed an inhibitory activity stronger than and equal to the representative SIRT inhibitor, nicotinamide (5), respectively. In support for this finding, SIRT1 was pulled down from the Neuro 2a lysate with arecaidine (2) immobilized on the FG NH2-beads, and accumulated acetyl-lysine was detected from the lysate of arecoline (1)-incubated Neuro 2a cells. Additionally, alkaloid 1 showed a neurite outgrowth effect though at the concentration range which did not inhibit SIRT1–3. ConclusionWe found out that arecoline (1) had the SIRT1–3 inhibition activities higher than the typical SIRT inhibitor, nicotinamide (5), while arecaidine (2) had the activities comparable to those of 5. Additionally, we disclosed that alkaloid 1 has another beneficial effect, the neurite outgrowth activity, though not related to SIRT inhibitory activity.

Design, Synthesis and Neurite Outgrowth Activity of Novel Ganglioside GM1 Derivatives by Remodeling of the Fatty Acid Moiety

Design, Synthesis and Neurite Outgrowth Activity of Novel Ganglioside GM1 Derivatives by Remodeling of the Fatty Acid Moiety

GPR3 accelerates neurite outgrowth and neuronal polarity formation via PI3 kinase-mediating signaling pathway in cultured primary neurons

During neuronal development, immature neurons extend neurites and subsequently polarize to form an axon and dendrites. We have previously reported that G protein-coupled receptor 3 (GPR3) levels increase during neuronal development, and that GPR3 has functions in neurite outgrowth and neuronal differentiation in cerebellar granular neurons. Moreover, GPR3 is transported and concentrated at the tips of neurite, thereby contributing to the local activation of protein kinase A (PKA). However, the signaling pathways for GPR3-mediated neurite outgrowth and its subsequent effects on neuronal polarization have not yet been elucidated. We therefore analyzed the signaling pathways related to GPR3-mediated neurite outgrowth, and also focused on the possible roles of GPR3 in axon polarization. We demonstrated that, in cerebellar granular neurons, GPR3-mediated neurite outgrowth was mediated by multiple signaling pathways, including those of PKA, extracellular signal-regulated kinases (ERKs), and most strongly phosphatidylinositol 3-kinase (PI3K). In addition, the GPR3-mediated activation of neurite outgrowth was associated with G protein-coupled receptor kinase 2 (GRK2)-mediated signaling and phosphorylation of the C-terminus serine/threonine residues of GPR3, which affected downstream protein kinase B (Akt) signaling. We further demonstrated that GPR3 was transiently increased early in the development of rodent hippocampal neurons. It was subsequently concentrated at the tip of the longest neurite, and was thus associated with accelerated polarity formation in a PI3K-dependent manner in rat hippocampal neurons. In addition, GPR3 knockout in mouse hippocampal neurons led to delayed neuronal polarity formation, thereby affecting the dephosphorylation of collapsing response mediator protein 2 (CRMP2), which is downstream of the PI3K signaling pathway. Taken together, these findings suggest that the intrinsic expression of GPR3 in differentiated neurons constitutively activates PI3K-mediated signaling pathway predominantly, thus accelerating neurite outgrowth and further augmenting polarity formation in primary cultured neurons.

Novel insights into the pathogenesis of DYT1 dystonia from induced patient-derived neurons.

Novel insights into the pathogenesis of DYT1 dystonia from induced patient-derived neurons.

Biosynthesis of Nonimmunosuppressive ProlylFK506 Analogues with Neurite Outgrowth and Synaptogenic Activity.

Separating the immunosuppressive activity of FK506 (1) from its neurotrophic activity is required to develop FK506 analogues as drugs for the treatment of neuronal diseases. Two new FK506 analogues, 9-deoxo-36,37-dihydro-prolylFK506 (2) and 9-deoxo-31-O-demethyl-36,37-dihydro-prolylFK506 (3) containing a proline moiety instead of the pipecolate ring at C-1 and modifications at the C-9/C-31 and C-36-C-37 positions, respectively, were biosynthesized, and their biological activities were evaluated. The proline substitution in 9-deoxo-36,37-dihydroFK506 and 9-deoxo-31-O-demethyl-36,37-dihydroFK506 reduced immunosuppressive activity by more than 120-fold, as previously observed. Compared with FK506 (1), 2 and 3 exhibited ∼1.2 × 105- and 2.2 × 105-fold reductions in immunosuppressive activity, respectively, whereas they retained almost identical neurite outgrowth activity. Furthermore, these compounds significantly increased the strength of synaptic transmission, confirming that replacement of the pipecolate ring with a proline is critical to reduce the strong immunosuppressive activity of FK506 (1) while enhancing its neurotrophic activity.

NRXN1 Depletion Induces Aberrant Locomotor Activity and Social Behavior Via Impairment of Neurite Outgrowth in Rat

NRXN1 Depletion Induces Aberrant Locomotor Activity and Social Behavior Via Impairment of Neurite Outgrowth in Rat

Potential Effects of Indole-3-Lactic Acid, a Metabolite of Human Bifidobacteria, on NGF-induced Neurite Outgrowth in PC12 Cells.

Gut microbiota-derived tryptophan metabolites such as indole derivatives are an integral part of host metabolome that could mediate gut–brain communication and contribute to host homeostasis. We previously reported that infant-type Human-Residential Bifidobacteria (HRB) produced higher levels of indole-3-lactic acid (ILA), suggesting the former might play a specific role in microbiota–host crosstalk by producing ILA in human infants. Nonetheless, the biological meaning of bifidobacteria-derived ILA in infant health development remains obscure. Here, we sought to explore the potential role of ILA in neuronal differentiation. We examined the neurite outgrowth and acetylcholinesterase (AchE) activity of PC12 cells following exposure to ILA and NGF induction. We found that ILA substantially enhanced NGF-induced neurite outgrowth of PC12 cells in a dose-dependent manner, and had the most prominent effect at 100 nM. Significant increases in the expression of TrkA receptor, ERK1/2 and CREB were observed in ILA-treated PC12 cells, suggesting ILA potentiated NGF-induced neurite outgrowth through the Ras/ERK pathway. Additionally, ILA was found to act as the aryl hydrocarbon receptor (AhR) agonist and evoked NGF-induced neurite outgrowth in an AhR-mediated manner. These new findings provide clues into the potential involvement of ILA as the mediator in bifidobacterial host–microbiota crosstalk and neuronal developmental processes.