bims-brabim 2022-01-02 papers

bims-brabim

Biomed News

on Brain bioenergetics and metabolism

Issue of 2022‒01‒02
23 papers selected by
João Victor Cabral-Costa
University of São Paulo

Exercise-induced metabolic changes in astrocytes in the 5xFAD mouse model of Alzheimer's Disease.
The role of SLC transporters for brain health and disease.
Astrocytic GLUT1 ablation improves systemic glucose metabolism and promotes cognition.
APOE4 derived from astrocytes leads to blood-brain barrier impairment.
Mitochondrial phenotypes in iPSC AD models.
Astroglial ER protein Membralin is an essential neuroinflammation regulator.
siRNA Mediated GSK3β Knockdown Targets Insulin Signaling Pathway and Rescues Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies.
Alzheimer's disease: A potential diabetes type 3.
Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer's Disease Model Mice.
lncRNA MIR600HG Knockdown Alleviates Cognitive Impairment in Alzheimer's Disease Through NEDD4L Mediated PINK1 Degradation.
Decreased O-GlcNAcylation and mitochondrial dysfunction are involving in low glucose induced Alzheimer's disease-like phenotype in induced pluripotent stem cell-derived neurons.
Therapeutic effects of stiripentol against ischemia-reperfusion injury in gerbils focusing on cognitive deficit, neuronal death, astrocyte damage and blood brain barrier leakage in the hippocampus.
Dissecting a neuron-to-liver crosstalk to modulate lipid metabolism in lisosomal storage diseases.
Neuronal contact upregulates astrocytic sphingosine-1-phosphate receptor 1 to coordinate astrocyte-neuron cross communication.
Mitochondrial disease manifestations in relation to transcriptome location and function.
Effects of Simultaneous Exposure to a Western Diet and Wheel-Running Training on Brain Energy Metabolism in Female Rats.
In Situ Imaging of Formaldehyde in Live Mice with High Spatiotemporal Resolution Reveals Aldehyde Dehydrogenase-2 as a Potential Target for Alzheimer's Disease Treatment.
Mitochondrial Function and Parkinson's Disease: From the Perspective of the Electron Transport Chain.
The Na+/Ca2+ Exchanger 3 Is Functionally Coupled With the NaV1.6 Voltage-Gated Channel and Promotes an Endoplasmic Reticulum Ca2+ Refilling in a Transgenic Model of Alzheimer's Disease.
Role of ketone bodies in diabetes-induced dementia: sirtuins, insulin resistance, synaptic plasticity, mitochondrial dysfunction, and neurotransmitter.
Defining the role of PLD3 in Alzheimer's disease pathology.
Intercellular transport of Tau protein and β-amyloid mediated by tunneling nanotubes.
Choline Supplementation Partially Restores Dendrite Structural Complexity in Developing Iron-Deficient Mouse Hippocampal Neurons.

Alzheimers Dement. 2021 Dec;17 Suppl 2 e058627

Exercise-induced metabolic changes in astrocytes in the 5xFAD mouse model of Alzheimer's Disease.

Sarah Alyssa Rosolen.

BACKGROUND: Alzheimer's Disease (AD), a progressive neurodegenerative disease and the second most common cause of death in Australia (ABS 2019), is an increasingly prominent societal issue, exacerbated by an ageing population and the absence of effective disease modifying treatments. Focus has shifted to targeting modifiable risk factors to slow or prevent AD onset and progression, such as exercise, diet and other lifestyle factors. Adiponectin, an anti-inflammatory adipokine, regulates energy metabolism and is associated with metabolic pathways potentiated following exercise. Animal and human studies involving both healthy individuals and those with metabolic dysfunction, have consistently demonstrated increased serum adiponectin levels following various exercise regimes. The ability of adiponectin to cross the blood brain barrier and thus mediate neuronal metabolism is contentious. However, the expression of adiponectin receptors within neuronal cells implies adiponectin holds an important function within the brain.METHODS: We investigated the cortical expression of adiponectin receptors, AdipoR1 and AdipoR2, in the aged 5XFAD mouse model of AD following an exercise intervention. Immunohistochemical techniques were applied to double stain brain tissue for adiponectin receptor and astrocyte expression.
RESULTS: We observed neuronal AdipoR1 and AdipoR2 expression throughout the cortex of both exercised and sedentary control mice, as well as extensive expression of activated astrocytes.
CONCLUSIONS: Colocalisation analysis suggests astrocytes may utilise adiponectin receptors to fuel their metabolic activity in degrading toxic amyloid plaques within the AD brain.

DOI: https://doi.org/10.1002/alz.058627
Cell Mol Life Sci. 2021 Dec 31. 79(1): 20

The role of SLC transporters for brain health and disease.

Yen T K Nguyen, Hoa T T Ha, Tra H Nguyen, Long N Nguyen.

  The brain exchanges nutrients and small molecules with blood via the blood-brain barrier (BBB). Approximately 20% energy intake for the body is consumed by the brain. Glucose is known for its critical roles for energy production and provides substrates for biogenesis in neurons. The brain takes up glucose via glucose transporters GLUT1 and 3, which are expressed in several neural cell types. The brain is also equipped with various transport systems for acquiring amino acids, lactate, ketone bodies, lipids, and cofactors for neuronal functions. Unraveling the mechanisms by which the brain takes up and metabolizes these nutrients will be key in understanding the nutritional requirements in the brain. This could also offer opportunities for therapeutic interventions in several neurological disorders. For instance, emerging evidence suggests a critical role of lactate as an alternative energy source for neurons. Neuronal cells express monocarboxylic transporters to acquire lactate. As such, treatment of GLUT1-deficient patients with ketogenic diets to provide the brain with alternative sources of energy has been shown to improve the health of the patients. Many transporters are present in the brain, but only a small number has been characterized. In this review, we will discuss about the roles of solute carrier (SLC) transporters at the blood brain barrier (BBB) and neural cells, in transport of nutrients and metabolites in the brain.

Keywords:  Blood-brain barrier; GLUT1; MCT1; Mfsd2a; SLC transporter

DOI:  https://doi.org/10.1007/s00018-021-04074-4
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058650

Astrocytic GLUT1 ablation improves systemic glucose metabolism and promotes cognition.

Carlos G Ardanaz, María Javier Ramírez Gil, Cristian Smerdou, Maite Solas.

BACKGROUND: Glucose supply from the blood to the brain is controlled by the glucose transporter GLUT1, highly expressed in astrocytes, which coordinate brain glucose supply, metabolization and storage. Ablating GLUT1 at the blood-brain barrier (BBB) endothelial cells leads to BBB breakdown, brain glucose hypometabolism and impaired cognition, but this approach cannot discriminate between insufficient glucose supply and BBB breakdown-derived effects. Such question is the focus of the present work, which aims to elucidate the relevance of astrocytic GLUT1 to cellular, brain and systemic glucose metabolism, and to cognition.METHODS: To address these questions, GLUT1 was ablated from primary astrocytes. Cellular metabolism was examined using an extracellular flux analyzer (Seahorse). In vivo, astrocytic GLUT1 was ablated using a tamoxifen-inducible Cre/LoxP approach (GLUT1ΔGFAP mice). 18 F-FDG PET, glucose and insulin tolerance and insulin secretion and fasting-induced hyperphagia were characterized. BBB integrity was examined by vessel immunostaining and capillary-depleted brain analysis. Recognition and spatial memory were assessed using Novel Object Recognition and Morris Water Maze tasks. To address the implication of purinergic signaling in those effects, a purinergic receptor antagonist (PPADS) was intracerebroventricularly administered before each behavioral test.
RESULTS: GLUT1-ablated astrocytes showed reduced glucose uptake and glycolysis, although preserving total ATP production. Unexpectedly, postnatal astrocytic GLUT1 deletion increased CNS glucose utilization. GLUT1ΔGFAP mice showed an improved metabolic status from which obese animals especially benefited. Specifically, GLUT1ΔGFAP mice were more efficient at suppressing hyperphagia and readjusting systemic glucose levels after hyperglycemia, exhibiting marked increase in insulin secretion. These effects were coupled with enhanced BAT activity, and reduced BAT adiposity. In parallel with this improved systemic homeostasis, GLUT1ΔGFAP mice performed both recognition and spatial memory tasks properly, even outperforming control mice. Noteworthy, those effects could be due to higher astrocytic ATP release. Indeed, central administration of PPADS could reverse improvements in metabolic and cognitive behaviors in mice with astrocyte GLUT1 knockout.
CONCLUSION: Overall, this study demonstrates that astrocytic GLUT1 ablation impairs astrocytic glucose availability but enhances brain glucose utilization, reprograms systemic glucose metabolism towards a more efficient glucose-handling phenotype and promotes cognitive abilities, which could be a key factor in neurodegenerative diseases such as Alzheimer's disease.

DOI: https://doi.org/10.1002/alz.058650
Brain. 2021 Dec 27. pii: awab478. [Epub ahead of print]

APOE4 derived from astrocytes leads to blood-brain barrier impairment.

Rosemary J Jackson, Jonah C Meltzer, Huong Nguyen, Caitlin Commins, Rachel E Bennett, Eloise Hudry, Bradley T Hyman.

  Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, and in the periphery largely by the liver. ApoE has been shown to impact the integrity of the blood brain barrier, and, in humans, the APOE4 allele of the gene is reported to lead to a leaky blood brain barrier. We used allele specific knock-in mice expressing each of the common (human) ApoE alleles, and longitudinal multiphoton intravital microscopy, to directly monitor the impact of various ApoE isoforms on blood brain barrier integrity. We found that humanized APOE4, but not APOE2 or APOE3, mice show a leaky blood brain barrier, increased MMP9, impaired tight junctions, and reduced astrocyte end-foot coverage of blood vessels. Removal of astrocyte-produced ApoE4 led to the amelioration of all phenotypes while the removal of astrocyte-produced ApoE3 had no effect on blood brain barrier integrity. This work shows a cell specific gain of function effect of ApoE4 in the dysfunction of the BBB and implicates astrocyte production of ApoE4, possibly as a function of astrocytic end foot interactions with vessels, as a key regulator of the integrity of the blood brain barrier.

Keywords:  Alzheimer disease; apolipoprotein E; astrocytes; blood–brain barrier

DOI:  https://doi.org/10.1093/brain/awab478
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058489

Mitochondrial phenotypes in iPSC AD models.

Kaitlin Flannagan, Julia A Stopperan, Benjamin M Troutwine, Colton R Lysaker, Taylor Strope, Julia Draper, Cynthia Shaddy-Gouvion, Jay Vivian, Mohammad Haeri, Heather M Wilkins.

BACKGROUND: Mitochondrial dysfunction is observed in Alzheimer's disease (AD). Altered mitochondrial respiration, cytochrome oxidase (COX) Vmax, and mitophagy are observed in human subjects and animal models of AD. Models derived from induced pluripotent stem cells (iPSCs) may not recapitulate these phenotypes after reprogramming from differentiated adult cells. We examined mitochondrial function across iPSC derived models including cerebral organoids, forebrain neurons, and astrocytes. Postmortem brain tissue was used as a comparison.METHOD: iPSCs were reprogrammed from fibroblasts either from the University of Kansas Alzheimer's Disease Research Center (KU ADRC) cohort or purchased from WiCell. Postmortem brain samples were from the KU ADRC cohort when available. A total of four non-demented and four sporadic AD iPSC lines were examined. Postmortem brain tissue was derived from 9 ND and 12 AD subjects. iPSCs were differentiated into neurons, astrocytes, or cerebral organoids using StemCell Technologies protocols and reagents. iPSC derived models and postmortem brain tissue were subjected to mitochondrial respiration analysis using Seahorse XF technology and spectrophotometric COX Vmax assays. iPSC derived neurons and astrocytes underwent fluorescent assays to determine mitochondrial mass, mitochondrial membrane potential, and mitophagy levels.
RESULT: iPSC derived neurons and cerebral organoids showed reduced COX Vmax in AD subjects. These results were not observed in astrocytes. Postmortem human brain samples showed reduced COX Vmax in AD subjects. iPSC derived neurons had reduced mitochondrial respiration parameters, mitochondrial mass, mitophagy, mitochondrial membrane potential, and mitochondrial superoxide production. iPSC derived astrocytes had reduced mitochondrial respiration parameters but increased mitochondrial membrane potential and no change in mitochondrial superoxide production.
CONCLUSION: iPSC derived models from AD subjects show mitochondrial dysfunction phenotypes like what is observed in postmortem brain. As iPSCs do not maintain their epigenetic signatures after reprogramming the observed phenotypes are likely due to other somatic factors.

DOI: https://doi.org/10.1002/alz.058489
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058566

Astroglial ER protein Membralin is an essential neuroinflammation regulator.

LuLin Jiang, Xiaoguang Li, Stephanie Myers, Timothy Huang, Randal J Kaufman.

BACKGROUND: The endoplasmic reticulum (ER) is the primary organelle for synthesizing membrane proteins, secretory proteins, and lipids. Disturbance of ER homeostasis in peripheral immune cells is associated with inflammatory responses. Glial cells, including astrocytes and microglia, are the immune cells in the brains, becoming reactive/gliosis during the progression of Alzheimer's disease (AD). However, whether and how glial protein homeostasis mediate the reactive state of glial cells is yet to be investigated. We previously identified a novel ER-associated degradation component, membralin/TMEM259, as an important mediator in neurodegeneration. Loss of membralin impaired the turnover of nicastrin protein, which increased gamma-secretase complex formation and activity. Knockdown membralin in the TgCRND8-AD mice exaggerated beta-amyloid-associated neuronal damage. Moreover, selective deletion of membralin in astrocytes decreased excitatory amino acid transporter 2 (EAAT2) expression and induced excitotoxicity. Elevating membralin levels in SOD1 G93A ALS mouse model can significantly extend the lifespan of the animals.METHOD: Transcriptomic profiles of the cortex tissues and histology were analyzed in the astrocyte-conditional membralin knockout animals. Primary astrocyte ER morphology was examined by electron microscopy analysis. We crossed the transgenic membralin animals with 5xFAD animals and assessed the AD pathology.
RESULT: Astroglial membralin knockout animals develop strong neuroinflammation phenotypes. Loss of membralin in astrocytes disrupts ER homeostasis and nuclear envelop integrity, and induces senescence-like phenotypes. In contrast, the elevation of membralin in astrocytes can alleviate the induction of C3+ astrocytes upon c1q/IL1a/TNFa treatment. Further, elevating membralin levels in 5XFAD mouse model can significantly reduce the AD pathologies.
CONCLUSION: Membralin is critical in mediating the reactive states of astrocytes. Modulation of astroglial ER homeostasis can be a promising target to regulate neuroinflammation for AD therapy.

DOI: https://doi.org/10.1002/alz.058566
ACS Appl Mater Interfaces. 2021 Dec 30.

siRNA Mediated GSK3β Knockdown Targets Insulin Signaling Pathway and Rescues Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies.

Smriti Gupta, Vishal Singh, Subramaniam Ganesh, Nitin K Singhal, Rajat Sandhir.

  Sporadic Alzheimer's disease (sAD) is a progressive neurodegenerative disorder with dysfunctional insulin signaling and energy metabolism. Emerging evidence suggests impairments in brain insulin responsiveness, glucose utilization, and energy metabolism may be major causes of amyloid precursor protein mishandling. The support for this notion comes from the studies wherein streptozotocin (STZ) induced brain insulin resistance in rodent model resulted in sAD-like neuropathology with cognitive decline. Our previous study showed a compromised insulin signaling pathway, glucose uptake, glucose metabolism, and energy homeostasis in STZ-induced glial-neuronal coculture and in vivo model of sAD. Various components of insulin signaling pathway were examined to understand the metabolic correlation, and GSK3β was selected for gene knockdown strategy to reverse sAD pathology based on the data. In the present study, we have synthesized carboxylated graphene oxide (GO) nanosheets functionalized with PEG and subsequently with polyethylenimine (PEI) to provide attachment sites for GSK3β siRNA. Our results showed that siRNA mediated knockdown of the GSK3β gene reduced expression of amyloid pathway genes (APP and BACE1), which was further confirmed by reduced amyloid beta (Aβ) levels in the in vitro STZ-induced sAD model. GSK3β knockdown also restored insulin signaling, AMPK and Mapk3 pathway by restoring the expression of corresponding candidate genes in these pathways (IR, Glut1/3, Prkaa1/2, Mapk3, BDNF) that reflected improved cellular energy homeostasis, neuronal proliferation, differentiation, maturation, and repair. Behavioral data from Morris water maze (MWM), open field (OF), novel object recognition (NOR), Y maze, and radial arm maze (RAM) tests showed that 0.5 μg nanoformulation (GOc-PP-siRNAGSK3β) intranasally for 7 days improved spatial memory, rescued anxiety like behavior, improved visual and working memory, and rescued exploratory behavior in STZ-induced sAD rats. GSK3β silencing resulted in decreased BACE1 expression and prevented accumulation of Aβ in the cortex and hippocampus. These molecular findings with improved behavioral performances were further correlated with reduced amyloid beta (Aβ) and neurofibrillary tangle (NFTs) formation in the cortex and hippocampus of GOc-PP-siRNAGSK3β administered sAD rats. Therefore, it is conceivable from the present study that nanoparticle-mediated targeting of GSK3β in the sAD appears to be a promising strategy to reverse sAD pathology.

Keywords:  Alzheimer’s disease; GSK3β; glia; graphene oxide; insulin; nanodelivery

DOI:  https://doi.org/10.1021/acsami.1c15305
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058533

Alzheimer's disease: A potential diabetes type 3.

Andrea González, Calfio Camila, Ricardo Benjamin Maccioni.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism dysregulation has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes.METHODS: Within this revised topic, we provide an analysis regarding the influence of glucose metabolism in AD from three different perspectives: i) As a regulator of the energy source, ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence the activation of the immune system (e.g., insulin resistance, diabetes, etc.) and iii) as modulators of various key post-translational modifications for protein aggregation.
RESULTS: During our research, it was demonstrated the relationship between glucose metabolism dysregulation and the onset and Alzheimer's disease: The latter is mediated by several metabolic alterations. Among those, included in our research, are metabolic dysregulation events (e.g insulin resistance), which in turn alters the proper ATP generation, and finally, post-translational modifications, e.g., glycosylation and phosphorylation that mediates protein aggregation (i.e tau hyperphosphorylation that leads to misfolding and pathological self-assembly).
CONCLUSIONS: Alzheimer's disease onset and development is related to a glucose metabolism impairment that affects energy source (ATP) regulation, several metabolic alterations such as insulin resistance, and mediator of post-translational modifications in key proteins (i.e tau) that promotes its self-assembly and aggregation. Thus, considering all the above mentioned, is it seems plausible to consider Alzheimer as the diabetes type 3.

DOI: https://doi.org/10.1002/alz.058533
Front Aging Neurosci. 2021 ;13 748388

Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer's Disease Model Mice.

Afzal Misrani, Sidra Tabassum, Qingwei Huo, Sumaiya Tabassum, Jinxiang Jiang, Adeel Ahmed, Xiangmao Chen, Jianwen Zhou, Jiajia Zhang, Sha Liu, Xiaoyi Feng, Cheng Long, Li Yang.

  Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

Keywords:  Alzheimer’s disease; hippocampus; medial prefrontal cortex; mitochondrial dynamics; social interaction

DOI:  https://doi.org/10.3389/fnagi.2021.748388
J Alzheimers Dis. 2021 Dec 22.

lncRNA MIR600HG Knockdown Alleviates Cognitive Impairment in Alzheimer's Disease Through NEDD4L Mediated PINK1 Degradation.

Qingqing Liu, Zaisheng Ling, Jinpeng Zhang, Hongli Yu, Ye Wang, Yang Xue, Chunyan Wang, Jiwei Zhao, Jingwei Cao, Shurong Duan, Jingkun Zhao.

  BACKGROUND: Growing evidence has demonstrated that long non-coding RNAs (lncRNAs) play a critical role in Alzheimer's disease (AD), which is characterized by sustained mitochondrial dysfunction, inevitable memory loss, and cognitive decline. However, the potential function of lncRNAs MIR600 Host Gene (MIR600HG) in AD remains unanswered.OBJECTIVE: Our study aimed to investigate the role of MIR600HG and its related molecular mechanism in AD.
METHODS: The expression of MIR600HG was examined by qRT-PCR. The MIR600HG interacting proteins were identified by RNA pull-down assay and mass spectrometry and verified by RNA immunoprecipitation. Immunofluorescence staining was applied to examine the colocalization of PINK1 and NEDD4L. The PINK1 level and the activation of autophagy were detected by immunoblotting. Morris water maze test was performed to evaluate cognitive decline in AD mice model.
RESULTS: MIR600HG expression was elevated during aging in two different types of AD transgenic mouse models. Next, we found that increased MIR600HG directly interact with NEDD4L, which promoted PINK1 ubiquitination and degradation, and as well as autophagy activation. Additionally, MIR600HG promoted Aβ production and suppressed Cytochrome C Oxidase activity. Administration of AAV-shMIR600HG restored the Cytochrome C Oxidase activity and inhibited Aβ production. Furthermore, PINK1 overexpression or MIR600HG knockdown significantly ameliorated the cognitive impairment in APP/PS1 mice. PINK1 depletion recovered the spatial memory defect in the AAV-shMIR600HG injected APP/PS1 mice.
CONCLUSION: MIR600HG was increased in AD and promoted AD pathogenesis. Targeting MIR600HG significantly improved cognitive function in AD mice, which could pave the way for exciting new avenues in AD therapeutic strategy research.

Keywords:  Alzheimer’s disease; PINK1; autophagy; lncRNAs MIR600HG; mitochondrial dysfunction

DOI:  https://doi.org/10.3233/JAD-215194
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058620

Decreased O-GlcNAcylation and mitochondrial dysfunction are involving in low glucose induced Alzheimer's disease-like phenotype in induced pluripotent stem cell-derived neurons.

Chia-Wei Huang, Gerald W Hart.

BACKGROUND: Evidence supporting that glucose metabolic abnormalities occur prior to Alzheimer's disease (AD) symptoms. Reduced O-GlcNAc (OGN) levels likely arise from impaired glucose metabolism or availability and correlates with AD pathogenesis. So far, the mechanism of sAD and the role of OGN in AD pathology remained largely unknown due to a lack of human sAD model.METHOD: We generated human cortical neurons from human-induced pluripotent stem cells and treated neurons with glucose reduction media. FluoroJADE staining and cell viability assays were used to study the effects of low glucose on the degenerative status and cell viability of neurons. Abnormal protein production, phosphorylation, and accumulation were detected by western blotting and immunofluorescence staining using antibody against p-tau and beta-amyloid. Neurite and synaptic structure were observed by immunofluorescence staining, while neuronal network activity was detected by multi-electrode array electrophysiological analyses. Mitochondrial abnormalities, including increased oxidative stress, reduced membrane potential, and mitochondrial dysfunction, were evaluated using CM-H2 DCFDA, JC-1 and Seahorse, respectively.
RESULT: We show that lowering glucose level to 2mM leads to dramatic increases of neuron degeneration on day 3 and 5 of treatment and decreased cell viability on day 7. Interestingly, long-term low glucose treatment induces AD features in neurons, including abnormal hyperphosphorylated tau accumulation and increasing beta-amyloid production. Besides, glucose deficiency also causes decreased neurite coverage, synapse density, and neuron network activity. Furthermore, we find that O-GlcNAc levels are significantly reduced soon after low glucose treatment and remain low until the end of experiment. Raising O-GlcNAc levels by thiamet-G, inhibitor of O-GlcNAcase, even in low glucose treated neurons, rescues low glucose-induced AD phenotypes. Moreover, our data shows that O-GlcNAc dysregulation causes mitochondrial abnormalities, which occur before any other degenerative phenotype appeared, and may be one of the underlying mechanisms of sAD onset and pathogenesis.
CONCLUSION: We established a human neuron model in which the pathological features are reproduced by glucose deficiency. This platform can serve as a tool for better understanding molecular processes involved in neurodegeneration in sAD. Our results also suggest that dysregulated O-GlcNAc levels and mitochondrial dysfunction by glucose deficiency are involved in the onset and progression of sAD.

DOI: https://doi.org/10.1002/alz.058620
Korean J Physiol Pharmacol. 2022 Jan 01. 26(1): 47-57

Therapeutic effects of stiripentol against ischemia-reperfusion injury in gerbils focusing on cognitive deficit, neuronal death, astrocyte damage and blood brain barrier leakage in the hippocampus.

Myoung Cheol Shin, Tae-Kyeong Lee, Jae-Chul Lee, Hyung Il Kim, Chan Woo Park, Jun Hwi Cho, Dae Won Kim, Ji Hyeon Ahn, Moo-Ho Won, Choong-Hyun Lee.

  Stiripentol is an anti-epileptic drug for the treating of refractory status epilepticus. It has been reported that stiripentol can attenuate seizure severity and reduce seizure-induced neuronal damage in animal models of epilepsy. The objective of the present study was to investigate effects of post-treatment with stiripentol on cognitive deficit and neuronal damage in the cornu ammonis 1 (CA1) region of the hippocampus proper following transient ischemia in the forebrain of gerbils. To evaluate ischemia-induced cognitive impairments, passive avoidance test and 8-arm radial maze test were performed. It was found that post-treatment with stiripentol at 20 mg/kg, but not 10 or 15 mg/kg, reduced ischemia-induced memory impairment. Transient ischemia-induced neuronal death in the CA1 region was also significantly attenuated only by 20 mg/kg stiripentol treatment after transient ischemia. In addition, 20 mg/kg stiripentol treatment significantly decreased ischemia-induced astrocyte damage and immunoglobulin G leakage. In brief, stiripentol treatment after transient ischemia ameliorated transient ischemia-induced cognitive impairment in gerbils, showing that pyramidal neurons were protected and astrocyte damage and blood brain barrier leakage were significantly attenuated in the hippocampus. Results of this study suggest stiripentol can be developed as a candidate of therapeutic drug for ischemic stroke.

Keywords:  Blood-brain barrier; Brain ischemia; Hippocampus; Neuroprotection; Stiripentol

DOI:  https://doi.org/10.4196/kjpp.2022.26.1.47
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058600

Dissecting a neuron-to-liver crosstalk to modulate lipid metabolism in lisosomal storage diseases.

Marina Garcia-Macia, Juan Pedro Bolaños.

BACKGROUND: Neuronal ceroid lipofuscinoses (NCL), known as Batten disease, are the most common of the rare neurodegenerative disorders in children. To date, defects in thirteen different genes have been identified in NCL patients. Despite the genetic heterogeneity, Batten diseases are grouped together based on clinical similarities and broadly uniform neuropathological features, including accumulation of lipofuscin in lysosomes, as well as profound neurodegeneration and widespread gliosis. Amongst these, the incidence of Cln7 disease, caused by mutation in MFSD8 gene, is the highest in southern and Mediterranean Europe. CLN7/MFSD8 encodes a lysosomal membrane glycoprotein with unknown function. Lysosomes are the only organelles able to hydrolyse triacylglycerols, which fuels the mitochondria for energy generation. The autophagic machinery provides TGs to the lysosomes through a process known as lipophagy. Although defective autophagy has been related with Cln7 disease, Cln7 role in lipid metabolism is unknown, particularly in lipophagy. Here, we hypothesized that disruption of lipophagy links neuronal death and Cln7-mediated Batten disease.METHOD: To address this, we have studied lipophagy in Cln7 knockout (Cln7-KO) mice and investigated whether Cln7 loss in the hypothalamus disrupts liver lipophagy. We have obtained experimental data from different techniques in Cln7-KO mice fibroblasts, liver, brown fat and brain, to stablish a connection between the brain and the metabolism of the peripheral tissues.
RESULT: Thus, our data show that Cln7 deficiency in the hypothalamus damages liver lipophagy resulting in fat accumulation. Ongoing work is being developed to validate these observations using robust metabolic and in vivo uncoupling approaches.
CONCLUSION: Cln7 deficiency causes neuronal damages which seem to produce lipophagy impairment in the periphery tissues.

DOI: https://doi.org/10.1002/alz.058600
Glia. 2021 Dec 27.

Neuronal contact upregulates astrocytic sphingosine-1-phosphate receptor 1 to coordinate astrocyte-neuron cross communication.

Sandeep K Singh, Tomasz Kordula, Sarah Spiegel.

  Astrocytes, the most abundant glial cells in the mammalian brain, directly associate with and regulate neuronal processes and synapses and are important regulators of brain development. Yet little is known of the molecular mechanisms that control the establishment of astrocyte morphology and the bi-directional communication between astrocytes and neurons. Here we show that neuronal contact stimulates expression of S1PR1, the receptor for the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P), on perisynaptic astrocyte processes and that S1PR1 drives astrocyte morphological complexity and morphogenesis. Moreover, the S1P/S1PR1 axis increases neuronal contact-induced expression of astrocyte secreted synaptogenic factors SPARCL1 and thrombospondin 4 that are involved in neural circuit assembly. Our findings have uncovered new functions for astrocytic S1PR1 signaling in regulation of bi-directional astrocyte-neuron crosstalk at the nexus of astrocyte morphogenesis and synaptogenesis.

Keywords:  astrocytes; sphingosine-1-phosphate; synaptogenic factors

DOI:  https://doi.org/10.1002/glia.24135
Mol Genet Metab. 2021 Dec 23. pii: S1096-7192(21)01193-8. [Epub ahead of print]

Mitochondrial disease manifestations in relation to transcriptome location and function.

Vikram Jakkamsetti, Seema Balasubramaniam, Nidhi Grover, Juan M Pascual.

  Localization within the nervous system provides context for neurological disease manifestations and treatment, with numerous disease mechanisms exhibiting predilect locations. In contrast, the molecular function of most disease-causing genes is generally considered dissociated from such brain regional correlations because most genes are expressed throughout the brain. We tested the factual basis for this dissociation by discerning between two distinct genetic disease mechanism possibilities: One, gene-specific, in which genetic disorders are poorly localizable because they are multiform at the molecular level, with each mutant gene acting more widely or complexly than via mere loss or gain of one function. The other, more general, where aspects shared by groups of genes such as membership in a gene set that sustains a concerted biological process accounts for a common or localizable phenotype. We analyzed mitochondrial substrate disorders as a paradigm of apparently heterogeneous diseases when considered from the point of view of their manifestations and individual function of their causal genes. We used publicly available transcriptomes, disease phenotypes published in peer-reviewed journals and Human Ontology classifications for 27 mitochondrial substrate metabolism diseases and analyzed if these disorders manifest common phenotypes and if this relates to common brain regions or cells as demarcated by their transcriptome. The most frequent phenotypic manifestations and brain structures involved were almost stereotypic regardless of the individual gene affected, correlating with the regional abundance of the transcriptome that served mitochondrial substrate metabolism. This also applied to the transcriptome of inhibitory neurons, which are dysfunctional in some mitochondrial diseases. This stands in contrast with resistance to dementia atrophy from other causes, which is known to also associate with greater expression of a similar fraction of the transcriptome. The results suggest that brain region or cell type dysfunction stemming from a broad process such as mitochondrial substrate metabolism is more relevant for disease manifestations than individual gene participation in specific molecular function.

Keywords:  Metabolism; Mitochondrial; Phenotype; Transcriptome

DOI:  https://doi.org/10.1016/j.ymgme.2021.12.008
Nutrients. 2021 Nov 26. pii: 4242. [Epub ahead of print]13(12):

Effects of Simultaneous Exposure to a Western Diet and Wheel-Running Training on Brain Energy Metabolism in Female Rats.

Marta Maria Nowacka-Chmielewska, Daniela Liśkiewicz, Konstancja Grabowska, Arkadiusz Liśkiewicz, Łukasz Marczak, Anna Wojakowska, Natalia Pondel, Mateusz Grabowski, Jarosław Jerzy Barski, Andrzej Małecki.

  BACKGROUND: In the pathogenesis of central nervous system disorders (e.g., neurodegenerative), an important role is attributed to an unhealthy lifestyle affecting brain energy metabolism. Physical activity in the prevention and treatment of lifestyle-related diseases is getting increasing attention.METHODS: We performed a series of assessments in adult female Long Evans rats subjected to 6 weeks of Western diet feeding and wheel-running training. A control group of lean rats was fed with a standard diet. In all experimental groups, we measured physiological parameters (animal weights, body composition, serum metabolic parameters). We assessed the impact of simultaneous exposure to a Western diet and wheel-running on the cerebrocortical protein expression (global proteomic profiling), and in the second part of the experiment, we measured the cortical levels of protein related to brain metabolism (Western blot).
RESULTS: Western diet led to an obese phenotype and induced changes in the serum metabolic parameters. Wheel-running did not reduce animal weights or fat mass but significantly decreased serum glucose level. The global proteome analysis revealed that the altered proteins were functionally annotated as they were involved mostly in metabolic pathways. Western blot analysis showed the downregulation of the mitochondrial protein-Acyl-CoA dehydrogenase family member 9, hexokinase 1 (HK1)-enzyme involved in principal glucose metabolism pathways and monocarboxylate transporter 2 (MCT2). Wheel-running reversed this decline in the cortical levels of HK1 and MCT2.
CONCLUSION: The cerebrocortical proteome is affected by a combination of physical activity and Western diet in female rats. An analysis of the cortical proteins involved in brain energy metabolism provides a valuable basis for the deeper investigation of changes in the brain structure and function induced by simultaneous exposure to a Western diet and physical activity.

Keywords:  brain energy metabolism; female rats; global brain proteome; western diet; wheel-running training

DOI:  https://doi.org/10.3390/nu13124242
Anal Chem. 2021 Dec 28.

In Situ Imaging of Formaldehyde in Live Mice with High Spatiotemporal Resolution Reveals Aldehyde Dehydrogenase-2 as a Potential Target for Alzheimer's Disease Treatment.

Rongrong Tao, Meihua Liao, Yuxiang Wang, Huan Wang, Yuhang Tan, Siyao Qin, Wenjing Wei, Chunzhi Tang, Xingguang Liang, Yifeng Han, Xin Li.

Alterations in formaldehyde (FA) homeostasis are associated with the pathology of Alzheimer's disease (AD). In vivo tracking of FA flux is important for understanding the underlying molecular mechanisms, but is challenging due to the lack of sensitive probes favoring a selective, rapid, and reversible response toward FA. In this study, we re-engineered the promiscuous and irreversible phenylhydrazines to make them selective and reversible toward FA by tuning their nucleophilicity. This effort resulted in PFM309, a selective (selectivity coefficient KFA,methylglyoxal = 0.06), rapid (t1/2 = 32 s at [FA] = 200 μM), and reversible fluorogenic probe (K = 6.24 mM-1) that tracks the FA flux in both live cells and live mice. In vivo tracking of the FA flux was realized by PFM309 imaging, which revealed the gradual accumulation of FA in the live mice brain during normal aging and its further increase in AD mice. We further identified the age-dependent loss of catabolism enzymes ALDH2 and ADH5 as the primary mechanism responsible for formaldehyde excess. Activating ALDH2 with the small molecular activator Alda1 significantly protected neurovascular cells from formaldehyde overload and consequently from impairment during AD progress both in vitro and in vivo. These findings revealed PFM309 as a robust tool to study AD pathology and highlight ALDH2 as a potential target for AD drug development.

DOI: https://doi.org/10.1021/acs.analchem.1c04520
Front Mol Neurosci. 2021 ;14 797833

Mitochondrial Function and Parkinson's Disease: From the Perspective of the Electron Transport Chain.

Jeng-Lin Li, Tai-Yi Lin, Po-Lin Chen, Ting-Ni Guo, Shu-Yi Huang, Chun-Hong Chen, Chin-Hsien Lin, Chih-Chiang Chan.

  Parkinson's disease (PD) is known as a mitochondrial disease. Some even regarded it specifically as a disorder of the complex I of the electron transport chain (ETC). The ETC is fundamental for mitochondrial energy production which is essential for neuronal health. In the past two decades, more than 20 PD-associated genes have been identified. Some are directly involved in mitochondrial functions, such as PRKN, PINK1, and DJ-1. While other PD-associate genes, such as LRRK2, SNCA, and GBA1, regulate lysosomal functions, lipid metabolism, or protein aggregation, some have been shown to indirectly affect the electron transport chain. The recent identification of CHCHD2 and UQCRC1 that are critical for functions of complex IV and complex III, respectively, provide direct evidence that PD is more than just a complex I disorder. Like UQCRC1 in preventing cytochrome c from release, functions of ETC proteins beyond oxidative phosphorylation might also contribute to the pathogenesis of PD.

Keywords:  Parkinson’s disease; apoptosis; electron transport chain; mitochondria quality control; mitophagy

DOI:  https://doi.org/10.3389/fnmol.2021.797833
Front Pharmacol. 2021 ;12 775271

The Na+/Ca2+ Exchanger 3 Is Functionally Coupled With the NaV1.6 Voltage-Gated Channel and Promotes an Endoplasmic Reticulum Ca2+ Refilling in a Transgenic Model of Alzheimer's Disease.

Ilaria Piccialli, Roselia Ciccone, Agnese Secondo, Francesca Boscia, Valentina Tedeschi, Valeria de Rosa, Pasquale Cepparulo, Lucio Annunziato, Anna Pannaccione.

  The remodelling of neuronal ionic homeostasis by altered channels and transporters is a critical feature of the Alzheimer's disease (AD) pathogenesis. Different reports converge on the concept that the Na+/Ca2+ exchanger (NCX), as one of the main regulators of Na+ and Ca2+ concentrations and signalling, could exert a neuroprotective role in AD. The activity of NCX has been found to be increased in AD brains, where it seemed to correlate with an increased neuronal survival. Moreover, the enhancement of the NCX3 currents (INCX) in primary neurons treated with the neurotoxic amyloid β 1-42 (Aβ1-42) oligomers prevented the endoplasmic reticulum (ER) stress and neuronal death. The present study has been designed to investigate any possible modulation of the INCX, the functional interaction between NCX and the NaV1.6 channel, and their impact on the Ca2+ homeostasis in a transgenic in vitro model of AD, the primary hippocampal neurons from the Tg2576 mouse, which overproduce the Aβ1-42 peptide. Electrophysiological studies, carried in the presence of siRNA and the isoform-selective NCX inhibitor KB-R7943, showed that the activity of a specific NCX isoform, NCX3, was upregulated in its reverse, Ca2+ influx mode of operation in the Tg2576 neurons. The enhanced NCX activity contributed, in turn, to increase the ER Ca2+ content, without affecting the cytosolic Ca2+ concentrations of the Tg2576 neurons. Interestingly, our experiments have also uncovered a functional coupling between NCX3 and the voltage-gated NaV1.6 channels. In particular, the increased NaV1.6 currents appeared to be responsible for the upregulation of the reverse mode of NCX3, since both TTX and the Streptomyces griseolus antibiotic anisomycin, by reducing the NaV1.6 currents, counteracted the increase of the INCX in the Tg2576 neurons. In agreement, our immunofluorescence analyses revealed that the NCX3/NaV1.6 co-expression was increased in the Tg2576 hippocampal neurons in comparison with the WT neurons. Collectively, these findings indicate that NCX3 might intervene in the Ca2+ remodelling occurring in the Tg2576 primary neurons thus emerging as a molecular target with a neuroprotective potential, and provide a new outcome of the NaV1.6 upregulation related to the modulation of the intracellular Ca2+ concentrations in AD neurons.

Keywords:  Alzheimer’s disease; NCX3; Na+/Ca2+ exchanger; NaV1.6 channels; Tg2576 mice; hippocampal neurons

DOI:  https://doi.org/10.3389/fphar.2021.775271
Nutr Rev. 2021 Dec 27. pii: nuab118. [Epub ahead of print]

Role of ketone bodies in diabetes-induced dementia: sirtuins, insulin resistance, synaptic plasticity, mitochondrial dysfunction, and neurotransmitter.

Ji Yeon Chung, Oh Yoen Kim, Juhyun Song.

  Patients with type 2 diabetes can have several neuropathologies, such as memory deficits. Recent studies have focused on the association between metabolic imbalance and neuropathological problems, and the associated molecular pathology. Diabetes triggers neuroinflammation, impaired synaptic plasticity, mitochondrial dysfunction, and insulin resistance in the brain. Glucose is a main energy substrate for neurons, but under certain conditions, such as fasting and starvation, ketone bodies can be used as an energy fuel for these cells. Recent evidence has shed new light on the role of ketone bodies in regulating several anti-inflammation cellular pathways and improving glucose metabolism, insulin action, and synaptic plasticity, thereby being neuroprotective. However, very high amount of ketone bodies can be toxic for the brain, such as in ketoacidosis, a dangerous complication that may occur in type 1 diabetes mellitus or alcoholism. Recent findings regarding the relationship between ketone bodies and neuropathogenesis in dementia are reviewed in this article. They suggest that the adequately low amount of ketone bodies can be a potential energy source for the treatment of diabetes-induced dementia neuropathology, considering the multifaceted effects of the ketone bodies in the central nervous system. This review can provide useful information for establishing the therapeutic guidelines of a ketogenic diet for diabetes-induced dementia.

Keywords:  diabetes-induced dementia; insulin resistance; ketone bodies; mitochondrial dysfunction; neuroinflammation; sirtuins

DOI:  https://doi.org/10.1093/nutrit/nuab118
Alzheimers Dement. 2021 Dec;17 Suppl 2 e058730

Defining the role of PLD3 in Alzheimer's disease pathology.

Matthew J Rosene, Simon Hsu, Rita Martinez, Joanne Norton, Ping Yan, John R Cirrito, Jin-Moo Lee, Ana Maria Cuervo, Alison M Goate, Carlos Cruchaga, Celeste M Karch.

BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) in the brain. We recently identified coding variants in the phospholipase D3 (PLD3) gene that double the risk for late onset AD.METHOD: We examined the impact of PLD3 risk variants on PLD3 and Aβ metabolism using CRISPR/Cas9 in induced pluripotent stem cells (iPSC). We then modeled the PLD3 expression patterns observed in AD brains in immortalized cell and AD mouse models. Lysosomal function was assessed in human brain tissue.
RESULT: PLD3 A442A disrupts a splicing enhancer binding site and reduces PLD3 splicing in human brains. Differentiation of PLD3 A442A and isogenic control iPSCs into cortical neurons produced cells that were morphologically similar. At the molecular level, PLD3 A442A neurons displayed a similar defect in PLD3 splicing as was observed in human brains and a significant increase in Aβ42/Aβ40 compared with isogenic control lines. Thus, PLD3 A442A is sufficient to alter PLD3 splicing and Aβ metabolism. PLD3 expression was significantly lower in AD brains compared with controls, and PLD3 expression was highly correlated with expression of lysosomal genes. Thus, we sought to determine whether PLD3 contributes to Aβ accumulation in AD via disrupted Aβ metabolism. We found that overexpression of PLD3 in immortalized cells decreased Aβ levels while shRNA silencing of Pld3 increased Aβ levels. In an AD mouse model, overexpression of PLD3 in hippocampal neurons produced decreased interstitial fluid (ISF) Aβ levels and accelerated Aβ turnover. Conversely, knocking out Pld3 increased ISF Aβ, reduced Aβ turnover, and increased APP protein levels. Knocking out Pld3 overtime lead to altered amyloid morphology. To begin to determine whether PLD3 influences Aβ turnover via the lysosome, we isolated lysosomal fractions from human AD and control brains. PLD3 was enriched in lysosomal subfractions and PLD3 distribution in these subfractions was altered in AD. Furthermore, PLD3 stability in the lysosomal fractions was disrupted in AD brains.
CONCLUSION: Together, our findings demonstrate that PLD3 promotes Aβ clearance through pathways involving lysosomal degradation.

DOI: https://doi.org/10.1002/alz.058730
Am J Transl Res. 2021 ;13(11): 12509-12522

Intercellular transport of Tau protein and β-amyloid mediated by tunneling nanotubes.

Kejia Zhang, Zehui Sun, Xinyu Chen, Yifan Zhang, Angyang Guo, Yan Zhang.

Tunneling nanotubes (TNTs) are thin channel-like structures connecting distant cells, providing a route for intercellular communication. In this study, we investigated the physical properties, including the cytoskeletal components, length and diameter, of the TNTs formed by HEK293T, U87 MG, and U251 cell lines. We found that organelles such as lysosomes, mitochondria, and Golgi bodies can be transported through TNTs, indicating that TNTs can mediate material transport. Moreover, we investigated the transport of the Tau protein and β-amyloid (Aβ), which are both closely related to Alzheimer's disease (AD) pathology, through TNTs. The results showed that TNTs formed by various neuronal cell lines can mediate the transport of different forms of the Tau protein and fluorescently labeled Aβ and that this transport is bidirectional, with different velocities in various cell lines. Our results confirmed the transport of the Tau protein and Aβ between cells and provided a possible explanation for the cascade of cell death in specific brain regions during the progression of AD. Our findings suggest new possibilities for the treatment of AD.

Keywords: Alzheimer’s disease; Tau protein; tunneling nanotubes; β-amyloid
J Nutr. 2021 Dec 27. pii: nxab429. [Epub ahead of print]

Choline Supplementation Partially Restores Dendrite Structural Complexity in Developing Iron-Deficient Mouse Hippocampal Neurons.

Thomas W Bastian, William C von Hohenberg, Olivia R Kaus, Lorene M Lanier, Michael K Georgieff.

  BACKGROUND: Fetal-neonatal iron deficiency causes learning/memory deficits that persist after iron repletion. Simplified hippocampal neuron dendrite structure is a key mechanism underlying these long-term impairments. Early-life choline supplementation, with postnatal iron repletion, improves learning/memory performance in formerly iron-deficient (ID) rats.OBJECTIVE: To understand how choline improves iron deficiency-induced hippocampal dysfunction, we hypothesized that direct choline supplementation of ID hippocampal neurons may restore cellular energy production and dendrite structure.
METHODS: Embryonic mouse hippocampal neuron cultures were made ID with 9µM deferoxamine beginning at 3 days in vitro (DIV). At 11DIV, iron repletion (i.e., deferoxamine removal) was performed on a subset of ID cultures. These neuron cultures, and iron-sufficient (IS) control cultures, were treated with 30µM choline (or vehicle) between 11 and 18DIV. At 18DIV, the independent and combined effects of iron and choline treatments (two-factor ANOVA) on neuronal dendrite numbers, lengths and overall complexity and mitochondrial respiration and glycolysis were analyzed.
RESULTS: Choline treatment of ID neurons (ID+Cho) significantly increased overall dendrite complexity (150, 160, 180 and 210µm from the soma) compared to untreated ID neurons to a level that was no longer significantly different from IS neurons. The average and total length of primary dendrites in ID+Cho neurons were significantly increased by ∼15% compared to ID neurons, indicating choline stimulation of dendrite growth. Measures of mitochondrial respiration, glycolysis and ATP production rates were not significantly altered in ID+Cho neurons compared to ID neurons, remaining significantly reduced compared to IS neurons. Iron repletion significantly improved mitochondrial respiration, ATP production rates, overall dendrite complexity (100-180µm from the soma) and dendrite and branch lengths compared to untreated ID neurons.
CONCLUSIONS: Since choline partially restores dendrite structure in ID neurons without iron repletion, it may have therapeutic potential when iron treatment is not possible or advisable. Choline's mechanism in ID neurons requires further investigation.

Keywords:  ATP; Iron; brain development; choline; dendrites; energy metabolism; glycolysis; iron deficiency; mitochondria; neuron development; oxidative phosphorylation

DOI:  https://doi.org/10.1093/jn/nxab429