bims-medebr 2022-06-19 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–06–19
sixteen papers selected by
Regina F. Fernández, Johns Hopkins University

Metformin alleviates the cognitive impairment caused by aluminum by improving energy metabolism disorders in mice.
Amyloid Beta Peptide-Mediated Alterations in Mitochondrial Dynamics and its Implications for Alzheimer's Disease.
Ginsenoside Rb1 inhibits astrocyte activation and promotes transfer of astrocytic mitochondria to neurons against ischemic stroke.
Gestational exposure to bisphenol A induces region-specific changes in brain metabolomic fingerprints in sheep.
Organotypic whole hemisphere brain slice models to study the effects of donor age and oxygen-glucose-deprivation on the extracellular properties of cortical and striatal tissue.
Brain metabolic changes in patients with disseminated malignant melanoma under immunotherapy.
Dietary n-3 polyunsaturated fatty acid deficiency alters olfactory mucosa sensitivity in young mice but has no impact on olfactory behavior.
Loss of Drosophila NUS1 results in cholesterol accumulation and Parkinson's disease-related neurodegeneration.
Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction.
Mitochondrial Function and Dynamics in Neural Stem Cells and Neurogenesis: Implications for Neurodegenerative Diseases.
Amyloid-β impairs mitochondrial dynamics and autophagy in Alzheimer's disease experimental models.
Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.
Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.
Influence of Very-Long Chain Polyunsaturated Fatty Acids on Membrane Structure and Dynamics.
FTY720 decreases ceramides levels in the brain and prevents memory impairments in a mouse model of familial Alzheimer's disease expressing APOE4.
Liposomes: An emerging carrier for targeting Alzheimer's and Parkinson's diseases.

Biochem Pharmacol. 2022 Jun 11. pii: S0006-2952(22)00234-9. [Epub ahead of print] 115140

Metformin alleviates the cognitive impairment caused by aluminum by improving energy metabolism disorders in mice.

Yushuai Song, Ziyue Liu, Xiaoying Zhu, Chenyu Hao, Wudi Hao, Shengwen Wu, Jinghua Yang, Xiaobo Lu, Cuihong Jin.

  Long-term exposure to environmental aluminum was found to be related to the occurrence and development of neurodegenerative diseases. Energy metabolism disorders, one of the pathological features of neurodegenerative diseases, may occur in the early stage of the disease and are of potential intervention significance. Here, sub-chronic aluminum exposure mouse model was established, and metformin was used to intervene. We found that sub-chronic aluminum exposure decreased the protein levels of phosphorylation AMPK (p-AMPK), glucose transporter 1 (GLUT1) and GLUT3, taking charge of glucose uptake in the brain, reduced the levels of lactate shuttle-related proteins monocarboxylate transporter 4 (MCT4) and MCT2, as well as lactate content in the cerebral cortex, while increased hypoxia-inducible factor-1α (HIF-1α) level to drive downstream pyruvate dehydrogenase kinase 1 (PDK1) expression, thereby inhibiting pyruvate dehydrogenase (PDH) activity, and ultimately led to ATP depletion, neuronal death, and cognitive dysfunction. However, metformin could rescue these injuries. Thus, it came to a conclusion that aluminum could damage glucose uptake, interfere with astrocyte-neuron lactate shuttle (ANLS), interrupt the balance in energy metabolism, and resulting in cognitive function, while metformin has a neuroprotective effect against the disorder of energy metabolism caused by aluminum in mice.

Keywords:  HIF-1α; aluminum; astrocyte-neuron lactate shuttle (ANLS); energy metabolism disorder; metformin

DOI:  https://doi.org/10.1016/j.bcp.2022.115140
CNS Neurol Disord Drug Targets. 2022 Jun 16.

Amyloid Beta Peptide-Mediated Alterations in Mitochondrial Dynamics and its Implications for Alzheimer's Disease.

Luis Ángel Monsalvo-Maraver, Marisol Maya-López, Edgar Rangel-López, Isaac Túnez, Alexey A Tinkov, Anatoly Skalny, Beatriz Ferrer, Michael Aschner, Abel Santamarí.

  Alzheimer's disease (AD) is considered the most frequent neurodegenerative disorder worldwide, compromising cognitive function in patients, with an average incidence of 1-3% in the open population. Protein aggregation into amyloidogenic plaques and neurofibrillary tangles, as well as neurodegeneration in the hippocampal and cortical areas represent the neuropathological hallmarks of this disorder. Mechanisms involved in neurodegeneration include protein misfolding, augmented apoptosis, disrupted molecular signaling pathways and axonal transport, oxidative stress, inflammation, and mitochondrial dysfunction, among others. It is precisely through a disrupted energy metabolism that neural cells trigger toxic mechanisms leading to cell death. In this regard, the study of mitochondrial dynamics constitutes a relevant topic to decipher the role of mitochondrial dysfunction in neurological disorders, especially when considering that amyloid beta peptides can target mitochondria. Specifically, amyloid beta (Aβ) peptide, which is known to accumulate in the brain of AD patients, has been shown to disrupt overall mitochondrial metabolism by impairing energy production, mitochondrial redox activity, and calcium homeostasis, thus highlighting its key role for the AD pathogenesis. In this work, we review and discuss recent evidence supporting the concept that mitochondrial dysfunction mediated by amyloid peptides contributes to the development of AD.

Keywords:  Alzheimer’s disease.; Amyloid beta peptide; Energy metabolism alterations; Mitochondrial function; Mitophagy; Neurodegeneration; Protein aggregation

DOI:  https://doi.org/10.2174/1871527321666220616094036
Redox Biol. 2022 Jun 08. pii: S2213-2317(22)00135-5. [Epub ahead of print]54 102363

Ginsenoside Rb1 inhibits astrocyte activation and promotes transfer of astrocytic mitochondria to neurons against ischemic stroke.

Xue-Chun Ni, Hong-Fei Wang, Yuan-Yuan Cai, Dai Yang, Raphael N Alolga, Baolin Liu, Jia Li, Feng-Qing Huang.

  Astrocytes activation in response to stroke results in altered mitochondrial exchange with neurons. Ginsenoside Rb1is a major ginsenoside of Panax ginseng particularly known for its neuroprotective potential. This work aimed to investigate if Rb1 could rescue neurons from ischemic insult via astrocyte inactivation and mitochondrial transfer. We prepared conditioned astrocytes-derived medium for co-culture with neurons and examined the role of Rb1 in mitochondrial transfer from astrocytes to neurons. The neuroprotective potential of Rb1 was further confirmed in vivo using a mouse model of brain ischemia. In response to oxygen-glucose deprivation and reperfusion (OGD/R), astrocytes were reactivated and produced reactive oxygen species (ROS), an action that was blocked by Rb1. Mechanistically, Rb1 inhibited NADH dehydrogenase in mitochondrial complex I to block reverse electron transport-derived ROS production from complex I, and thus inactivated astrocytes to protect the mitochondria. Mitochondrial signal, mitochondrial membrane potential and ATP production detected in conditioned astrocyte-derived medium indicated that Rb1 protected functional mitochondria and facilitated their transfer. When neurons were injured by OGD/R insult, co-culturing with conditioned medium increased mitochondrial membrane potential and oxygen consumption rate within the neurons, indicating the protection conferred on them by Rb1 via mitochondrial transfer from astrocytes. Using the ischemic mouse brain model, CD38 knockdown in the cerebral ventricles diminished the neuroprotective effects of Rb1, providing evidence in support of the role of astrocyte mitochondrial transfer. Transient inhibition of mitochondrial complex I by Rb1 reduced mitochondrial ROS production and consequently avoided astrocyte activation. Astrocyte mitochondrial transfer therefore seemed a means by which Rb1 could promote neuronal survival and function. Different from the neurocentric view, these findings suggest the astrocytes may be a promising target for pharmacological interventions in ischemic brain injury.

Keywords:  Astrocyte reactivity; Ginsenoside Rb1; Mitochondrial transfer; Stroke

DOI:  https://doi.org/10.1016/j.redox.2022.102363
Environ Int. 2022 Jun 06. pii: S0160-4120(22)00263-X. [Epub ahead of print]165 107336

Gestational exposure to bisphenol A induces region-specific changes in brain metabolomic fingerprints in sheep.

Davy Guignard, Cécile Canlet, Marie Tremblay-Franco, Elodie Chaillou, Roselyne Gautier, Véronique Gayrard, Nicole Picard-Hagen, Henri Schroeder, Fabien Jourdan, Daniel Zalko, Catherine Viguié, Nicolas J Cabaton.

  Fetal brain development depends on maternofetal thyroid function. In rodents and sheep, perinatal BPA exposure is associated with maternal and/or fetal thyroid disruption and alterations in central nervous system development as demonstrated by metabolic modulations in the encephala of mice. We hypothesized that a gestational exposure to a low dose of BPA affects maternofetal thyroid function and fetal brain development in a region-specific manner. Pregnant ewes, a relevant model for human thyroid and brain development, were exposed to BPA (5 µg/kg bw/d, sc). The thyroid status of ewes during gestation and term fetuses at delivery was monitored. Fetal brain development was assessed by metabolic fingerprints at birth in 10 areas followed by metabolic network-based analysis. BPA treatment was associated with a significant time-dependent decrease in maternal TT4 serum concentrations. For 8 fetal brain regions, statistical models allowed discriminating BPA-treated from control lambs. Metabolic network computational analysis revealed that prenatal exposure to BPA modulated several metabolic pathways, in particular excitatory and inhibitory amino-acid, cholinergic, energy and lipid homeostasis pathways. These pathways might contribute to BPA-related neurobehavioral and cognitive disorders. Discrimination was particularly clear for the dorsal hippocampus, the cerebellar vermis, the dorsal hypothalamus, the caudate nucleus and the lateral part of the frontal cortex. Compared with previous results in rodents, the use of a larger animal model allowed to examine specific brain areas, and generate evidence of the distinct region-specific effects of fetal BPA exposure on the brain metabolome. These modifications occur concomitantly to subtle maternal thyroid function alteration. The functional link between such moderate thyroid changes and fetal brain metabolomic fingerprints remains to be determined as well as the potential implication of other modes of action triggered by BPA such as estrogenic ones. Our results pave the ways for new scientific strategies aiming at linking environmental endocrine disruption and altered neurodevelopment.

Keywords:  Bisphenol A; Environmental contaminants; Fetal exposure; Metabolomic; Neurodevelopment; Sheep

DOI:  https://doi.org/10.1016/j.envint.2022.107336
J Biol Eng. 2022 Jun 13. 16(1): 14

Organotypic whole hemisphere brain slice models to study the effects of donor age and oxygen-glucose-deprivation on the extracellular properties of cortical and striatal tissue.

Michael McKenna, Jeremy R Filteau, Brendan Butler, Kenneth Sluis, Michael Chungyoun, Nels Schimek, Elizabeth Nance.

   BACKGROUND: The brain extracellular environment is involved in many critical processes associated with neurodevelopment, neural function, and repair following injury. Organization of the extracellular matrix and properties of the extracellular space vary throughout development and across different brain regions, motivating the need for platforms that provide access to multiple brain regions at different stages of development. We demonstrate the utility of organotypic whole hemisphere brain slices as a platform to probe regional and developmental changes in the brain extracellular environment. We also leverage whole hemisphere brain slices to characterize the impact of cerebral ischemia on different regions of brain tissue.
RESULTS: Whole hemisphere brain slices taken from postnatal (P) day 10 and P17 rats retained viable, metabolically active cells through 14 days in vitro (DIV). Oxygen-glucose-deprivation (OGD), used to model a cerebral ischemic event in vivo, resulted in reduced slice metabolic activity and elevated cell death, regardless of slice age. Slices from P10 and P17 brains showed an oligodendrocyte and microglia-driven proliferative response after OGD exposure, higher than the proliferative response seen in DIV-matched normal control slices. Multiple particle tracking in oxygen-glucose-deprived brain slices revealed that oxygen-glucose-deprivation impacts the extracellular environment of brain tissue differently depending on brain age and brain region. In most instances, the extracellular space was most difficult to navigate immediately following insult, then gradually provided less hindrance to extracellular nanoparticle diffusion as time progressed. However, changes in diffusion were not universal across all brain regions and ages.
CONCLUSIONS: We demonstrate whole hemisphere brain slices from P10 and P17 rats can be cultured up to two weeks in vitro. These brain slices provide a viable platform for studying both normal physiological processes and injury associated mechanisms with control over brain age and region. Ex vivo OGD impacted cortical and striatal brain tissue differently, aligning with preexisting data generated in in vivo models. These data motivate the need to account for both brain region and age when investigating mechanisms of injury and designing potential therapies for cerebral ischemia.

Keywords:  Brain microenvironment; Brain slices; Extracellular; Nanoparticle diffusion; Organotypic; Particle tracking

DOI:  https://doi.org/10.1186/s13036-022-00293-w
Melanoma Res. 2022 Jun 15.

Brain metabolic changes in patients with disseminated malignant melanoma under immunotherapy.

Marina Sizova, Valle Camacho, Frederic Sampedro, Aida Sabaté-Llobera, Safae Abouzian, Patricia Stefaneli, Joan Duch, Alejandro Fernández-León, Diego Alfonso López-Mora, Montserrat Estorch, Ignasi Carrió, Albert Flotats.

Although there is evidence that chemotherapy can have side effects on metabolism and brain function, there are few studies on the occurrence of these side effects with immunotherapy. The present study was conducted to assess whether brain metabolic changes occur in patients with malignant melanoma under immunotherapy. Thirty-nine patients after surgical intervention and with a diagnosis of malignant melanoma were retrospectively included and were divided into two groups: one group under the first-line therapy with anti-programmed cell death-1 ± anti-cytotoxic T lymphocyte antigen-4 monoclonal antibodies and the other group without any treatment after surgery, which served as a control. Basal and follow-up whole body and brain 2-[18F]fluoro-2-deoxy-D-glucose (18F]FDG) PET/computed tomography (CT) studies were performed. Changes in brain glucose metabolism after treatment initiation of the immunotherapy group were compared with the findings in the control group. In addition, longitudinal regression analysis to investigate whether the time under immunotherapy influenced the changes of brain metabolism was performed. None of the patients presented cognitive impairment or other neurological alterations between basal and follow-up brain [18F]FDG PET/CT examinations. The statistical analysis revealed a significant relative SUV (SUVr)-loss in the left frontal region in patients of the immunotherapy group compared with the control group, with radjusted = -0.62 and P = 0.008. Severity of SUVr-loss was correlated with duration of treatment. Patients with disseminated malignant melanoma receiving immunotherapy may present a decrease of brain metabolism in the left frontal region, which is related with time-under-treatment, without any clinical evidence of neurological disorder.

DOI: https://doi.org/10.1097/CMR.0000000000000835
Nutr Neurosci. 2022 Jun 11. 1-14

Dietary n-3 polyunsaturated fatty acid deficiency alters olfactory mucosa sensitivity in young mice but has no impact on olfactory behavior.

Vanessa Soubeyre, Laetitia Merle, David Jarriault, Stéphane Grégoire, Lionel Bretillon, Niyazi Acar, Xavier Grosmaitre, Anne Marie Le Bon.

   BACKGROUND AND OBJECTIVE: We recently showed that perinatal exposure to diets with unbalanced n-6:n-3 polyunsaturated fatty acid (PUFA) ratios affects the olfactory mucosa (OM) fatty acid composition. To assess the repercussions of these modifications, we investigated the impact of diets unbalanced in n-3 PUFAs on the molecular composition and functionality of the OM in young mice.
METHODS: After mating, female mice were fed diets either deficient in α-linolenic acid (LOW diet) or supplemented with n-3 long-chain PUFAs (HIGH diet) during the perinatal period. Weaned male offspring were then fed ad libitum with the same experimental diets for 5 weeks. At 8 weeks of age, olfactory behavior tests were performed in young mice. The fatty acid composition of OM and olfactory cilia, as well as the expression of genes involved in different cellular pathways, were analyzed. The electroolfactograms induced by odorant stimuli were recorded to assess the impact of diets on OM functionality.
RESULTS AND CONCLUSION: Both diets significantly modified the fatty acid profiles of OM and olfactory cilia in young mice. They also induced changes in the expression of genes involved in olfactory signaling and in olfactory neuron maturation. The electroolfactogram amplitudes were reduced in mice fed the LOW diet. Nevertheless, the LOW diet and the HIGH diet did not affect mouse olfactory behavior. Our study demonstrated that consumption of diets deficient in or supplemented with n-3 PUFAs during the perinatal and postweaning periods caused significant changes in young mouse OM. However, these modifications did not impair their olfactory capacities.

Keywords:  Olfaction; electroolfactogram; fatty acid; maternal diet; mouse; olfactory behavior; olfactory cilia; olfactory mucosa

DOI:  https://doi.org/10.1080/1028415X.2022.2082642
FASEB J. 2022 07;36(7): e22411

Loss of Drosophila NUS1 results in cholesterol accumulation and Parkinson's disease-related neurodegeneration.

Jin Xue, Yingbao Zhu, Liyi Wei, Hongjing Huang, Guangxu Li, Wen Huang, Hua Zhu, Ranhui Duan.

  NgBR is the Nogo-B receptor, encoded by NUS1 gene. As NgBR contains a C-terminal domain that is similar to cis-isoprenyltransferase (cis-IPTase), NgBR was speculated to stabilize nascent Niemann-Pick type C 2 (NPC2) to facilitate cholesterol transport out of lysosomes. Mutations in the NUS1 were known as risk factors for Parkinson's disease (PD). In our previous study, it was shown that knockdown of Drosophila NUS1 orthologous gene tango14 causes decreased climbing ability, loss of dopaminergic neurons, and decreased dopamine contents. In this study, tango14 mutant flies were generated with a mutation in the C-terminal enzyme activity region using CRISPR/Cas9. Tango14 mutant showed a reduced lifespan with locomotive defects and cholesterol accumulation in Malpighian tubules and brains, especially in dopaminergic neurons. Multilamellar bodies were found in tango14 mutants using electron microscopy. Neurodegenerative-related brain vacuolization was also detected in tango14 knockdown flies in an age-dependent manner. In addition, tango14 knockdown increased α-synuclein (α-syn) neurotoxicity in α-syn-overexpressing flies, with decreased locomotive activities, dopamine contents, and the numbers of dopaminergic neurons in aging flies. Thus, these observations suggest a role of NUS1, the ortholog of tango14, in PD-related pathogenesis.

Keywords:   Drosophila ; Parkinson's disease; cholesterol accumulation; neurodegeneration

DOI:  https://doi.org/10.1096/fj.202200212R
Nat Commun. 2022 Jun 17. 13(1): 3490

Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction.

Zhenhua Liu, Nannan Yang, Jie Dong, Wotu Tian, Lisa Chang, Jinghong Ma, Jifeng Guo, Jieqiong Tan, Ao Dong, Kaikai He, Jingheng Zhou, Resat Cinar, Junbing Wu, Armando G Salinas, Lixin Sun, Mantosh Kumar, Breanna T Sullivan, Braden B Oldham, Vanessa Pitz, Mary B Makarious, Jinhui Ding, Justin Kung, Chengsong Xie, Sarah L Hawes, Lupeng Wang, Tao Wang, Piu Chan, Zhuohua Zhang, Weidong Le, Shengdi Chen, David M Lovinger, Cornelis Blauwendraat, Andrew B Singleton, Guohong Cui, Yulong Li, Huaibin Cai, Beisha Tang.

Endocannabinoid (eCB), 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain, regulates diverse neural functions. Here we linked multiple homozygous loss-of-function mutations in 2-AG synthase diacylglycerol lipase β (DAGLB) to an early onset autosomal recessive Parkinsonism. DAGLB is the main 2-AG synthase in human and mouse substantia nigra (SN) dopaminergic neurons (DANs). In mice, the SN 2-AG levels were markedly correlated with motor performance during locomotor skill acquisition. Genetic knockdown of Daglb in nigral DANs substantially reduced SN 2-AG levels and impaired locomotor skill learning, particularly the across-session learning. Conversely, pharmacological inhibition of 2-AG degradation increased nigral 2-AG levels, DAN activity and dopamine release and rescued the locomotor skill learning deficits. Together, we demonstrate that DAGLB-deficiency contributes to the pathogenesis of Parkinsonism, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neuronal activity and dopamine release, and suggest potential benefits of 2-AG augmentation in alleviating Parkinsonism.

DOI: https://doi.org/10.1038/s41467-022-31168-9
Ageing Res Rev. 2022 Jun 14. pii: S1568-1637(22)00109-X. [Epub ahead of print] 101667

Mitochondrial Function and Dynamics in Neural Stem Cells and Neurogenesis: Implications for Neurodegenerative Diseases.

Patrícia Coelho, Lígia Fão, Sandra Mota, A Cristina Rego.

  Mitochondria have been largely described as the powerhouse of the cell and recent findings demonstrate that this organelle is fundamental for neurogenesis. The mechanisms underlying neural stem cells (NSCs) maintenance and differentiation are highly regulated by both intrinsic and extrinsic factors. Mitochondrial-mediated switch from glycolysis to oxidative phosphorylation, accompanied by mitochondrial remodeling and dynamics are vital to NSCs fate. Deregulation of mitochondrial proteins, mitochondrial DNA, function, fission/fusion and metabolism underly several neurodegenerative diseases; data show that these impairments are already present in early developmental stages and NSC fate decisions. However, little is known about mitochondrial role in neurogenesis. In this Review, we describe the recent evidence covering mitochondrial role in neurogenesis, its impact in selected neurodegenerative diseases, for which aging is the major risk factor, and the recent advances in stem cell-based therapies that may alleviate neurodegenerative disorders-related neuronal deregulation through improvement of mitochondrial function and dynamics.

Keywords:  Mitochondria; Neural Stem Cells; Neurodegenerative Disorders; Neurogenesis

DOI:  https://doi.org/10.1016/j.arr.2022.101667
Sci Rep. 2022 Jun 16. 12(1): 10092

Amyloid-β impairs mitochondrial dynamics and autophagy in Alzheimer's disease experimental models.

Macarena de la Cueva, Desiree Antequera, Lara Ordoñez-Gutierrez, Francisco Wandosell, Antonio Camins, Eva Carro, Fernando Bartolome.

The most accepted hypothesis in Alzheimer's disease (AD) is the amyloid cascade which establishes that Aβ accumulation may induce the disease development. This accumulation may occur years before the clinical symptoms but it has not been elucidated if this accumulation is the cause or the consequence of AD. It is however, clear that Aβ accumulation exerts toxic effects in the cerebral cells. It is important then to investigate all possible associated events that may help to design new therapeutic strategies to defeat or ameliorate the symptoms in AD. Alterations in the mitochondrial physiology have been found in AD but it is not still clear if they could be an early event in the disease progression associated to amyloidosis or other conditions. Using APP/PS1 mice, our results support published evidence and show imbalances in the mitochondrial dynamics in the cerebral cortex and hippocampus of these mice representing very early events in the disease progression. We demonstrate in cellular models that these imbalances are consequence of Aβ accumulation that ultimately induce increased mitophagy, a mechanism which selectively removes damaged mitochondria by autophagy. Along with increased mitophagy, we also found that Aβ independently increases autophagy in APP/PS1 mice. Therefore, mitochondrial dysfunction could be an early feature in AD, associated with amyloid overload.

DOI: https://doi.org/10.1038/s41598-022-13683-3
Mol Neurodegener. 2022 06 11. 17(1): 41

Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.

Dan Xia, Steve Lianoglou, Thomas Sandmann, Meredith Calvert, Jung H Suh, Elliot Thomsen, Jason Dugas, Michelle E Pizzo, Sarah L DeVos, Timothy K Earr, Chia-Ching Lin, Sonnet Davis, Connie Ha, Amy Wing-Sze Leung, Hoang Nguyen, Roni Chau, Ernie Yulyaningsih, Isabel Lopez, Hilda Solanoy, Shababa T Masoud, Chun-Chi Liang, Karin Lin, Giuseppe Astarita, Nathalie Khoury, Joy Yu Zuchero, Robert G Thorne, Kevin Shen, Stephanie Miller, Jorge J Palop, Dylan Garceau, Michael Sasner, Jennifer D Whitesell, Julie A Harris, Selina Hummel, Johannes Gnörich, Karin Wind, Lea Kunze, Artem Zatcepin, Matthias Brendel, Michael Willem, Christian Haass, Daniel Barnett, Till S Zimmer, Anna G Orr, Kimberly Scearce-Levie, Joseph W Lewcock, Gilbert Di Paolo, Pascal E Sanchez.

   BACKGROUND: Genetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain.
METHODS: We engineered a novel App knock-in mouse model (AppSAA) using homologous recombination to introduce three disease-causing coding mutations (Swedish, Arctic and Austrian) to the mouse App gene. Amyloid-β pathology, neurodegeneration, glial responses, brain metabolism and behavioral phenotypes were characterized in heterozygous and homozygous AppSAA mice at different ages in brain and/ or biofluids. Wild type littermate mice were used as experimental controls. We used in situ imaging technologies to define the whole-brain distribution of amyloid plaques and compare it to other AD mouse models and human brain pathology. To further explore the microglial response to AD relevant pathology, we isolated microglia with fibrillar Aβ content from the brain and performed transcriptomics and metabolomics analyses and in vivo brain imaging to measure energy metabolism and microglial response. Finally, we also characterized the mice in various behavioral assays.
RESULTS: Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The AppSAA knock-in mouse model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered astroglial and microglial responses and elevation of CSF markers of neurodegeneration. Those observations were associated with increased TSPO and FDG-PET brain signals and a hyperactivity phenotype as the animals aged.
DISCUSSION: Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology.

Keywords:  Astrogliosis; Lipid dyshomeostasis; Neuritic plaques; Neurodegeneration; Phagocytic microglia; Vascular amyloid

DOI:  https://doi.org/10.1186/s13024-022-00547-7
Mol Neurodegener. 2022 Jun 15. 17(1): 42

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.

Shaowei Wang, Boyang Li, Victoria Solomon, Alfred Fonteh, Stanley I Rapoport, David A Bennett, Zoe Arvanitakis, Helena C Chui, Patrick M Sullivan, Hussein N Yassine.

   BACKGROUND: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.
METHODS: Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress.
RESULTS: Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of persons with AD dementia carrying APOE3/4 compared to APOE3/3. Higher phosphorylated p38 MAPK but not ERK1/2 was found in ApoE4 primary astrocytes and mouse brains than that in ApoE3. Greater cPLA2 translocation to cytosol was observed in human postmortem frontal cortical synaptosomes with recombinant ApoE4 than ApoE3 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition.
CONCLUSIONS: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

Keywords:  Alzheimer’s disease; ApoE4; Neuroinflammation; Oxidative stress; cPLA2; p38 MAPK

DOI:  https://doi.org/10.1186/s13024-022-00549-5
Biophys J. 2022 Jun 15. pii: S0006-3495(22)00474-X. [Epub ahead of print]

Influence of Very-Long Chain Polyunsaturated Fatty Acids on Membrane Structure and Dynamics.

Victoria Cheng, Rameshu Rallabandi, Aruna Gorusupudi, Steven Lucas, Gregory Rognan, Paul S Bernstein, Jon D Rainier, John C Conboy.

The unique attributes of very long chain polyunsaturated fatty acids (VLC-PUFAs), their long carbon chains (n >24) and high degree of unsaturation, impart unique chemical and physical properties to this class of fatty acids. The changes imparted by VLC-PUFA 32:6 n-3 on lipid packing and the compression moduli of model membranes were evaluated from π-A isotherms of VLC-PUFA in 1,2-distearoyl-sn-3-glycero-phosphocholine (DSPC) lipid monolayers. In order to compare the attractive or repulsive forces between VLC-PUFA and DSPC lipid monolayers, the measured mean molecular areas (MMAs) were compared to the calculated MMAs of an ideal mixture of VLC-PUFA and DSPC. The presence of 0.1 mol%, 1 mol%, and 10 mol% VLC-PUFA shifted the π-A isotherm to higher MMAs of the lipids comprising the membrane and the observed positive deviations from ideal behavior of the mixed VLC-PUFA:DSPC monolayers correspond to repulsive forces between VLC-PUFAs and DSPC. The MMA of the VLC-PUFA component was estimated using the measured MMAs of DSPC of 47.1 ± 0.7 Å2/molecule, to be 15000, 1100, and 91 Å2/molecule at 0.1 mol%, 1 mol%, and 10 mol% VLC-PUFA:DSPC mixtures, respectively. The large MMAs of VLC-PUFA suggest that the DHA tail reinserts into the membrane and adopts a non-linear structure in the membrane, which is most pronounced at 0.1 mol% VLC-PUFA. The presence of 0.1 mol% VLC-PUFA:DSPC also significantly increased the compression modulus of the membrane by 28 mN/m compared to a pure DSPC membrane. The influence of VLC-PUFA on lipid "flip-flop" was investigated by sum-frequency vibrational spectroscopy (SFVS). The incorporation of 0.1 mol% VLC-PUFA increased the DSPC flip-flop rate 4-fold. The fact that VLC-PUFA promotes lipid translocation is noteworthy as retinal membranes require a high influx of retinoids which may be facilitated by lipid flip-flop.

DOI: https://doi.org/10.1016/j.bpj.2022.06.015
Biomed Pharmacother. 2022 Jun 09. pii: S0753-3322(22)00629-1. [Epub ahead of print]152 113240

FTY720 decreases ceramides levels in the brain and prevents memory impairments in a mouse model of familial Alzheimer's disease expressing APOE4.

Simone M Crivelli, Qian Luo, Daan van Kruining, Caterina Giovagnoni, Marina Mané-Damas, Sandra den Hoedt, Dusan Berkes, Helga E De Vries, Monique T Mulder, Jochen Walter, Etienne Waelkens, Rita Derua, Johannes V Swinnen, Jonas Dehairs, Erwin P M Wijnands, Erhard Bieberich, Mario Losen, Pilar Martinez-Martinez.

  The protection mediated by the bioactive sphingolipid sphingosine-1-phosphate (S1P) declines during Alzheimer's disease (AD) progression, especially in patients carrying the apolipoprotein E ε4 (APOE4) isoform. The drug FTY720 mimics S1P bioactivity, but its efficacy in treating AD is unclear. Two doses of FTY720 (0.1 mg / kg and 0.5 mg / kg daily) were given by oral gavage for 15 weeks to transgenic mouse models of familial AD carrying human apolipoprotein E (APOE) APOE3 (E3FAD) or APOE4 (E4FAD). After 12 weeks of treatment, animals were subjected to behavioral tests for memory, locomotion, and anxiety. Blood was withdrawn at different time points and brains were collected for sphingolipids analysis by mass spectrometry, gene expression by RT-PCR and Aβ quantification by ELISA. We discovered that low levels of S1P in the plasma is associated with a higher probability of failing the memory test and that FTY720 prevents memory impairments in E4FAD. The beneficial effect of FTY720 was induced by a shift of the sphingolipid metabolism in the brain towards a lower production of toxic metabolites, like ceramide d18:1/16:0 and d18:1/22:0, and reduction of amyloid-β burden and inflammation. In conclusion, we provide further evidence of the druggability of the sphingolipid system in AD.

Keywords:  5xFAD; APOE3; APOE4; Anxiety; Ceramide; FTY720; Memory; S1P; Sphingomyelin

DOI:  https://doi.org/10.1016/j.biopha.2022.113240
Heliyon. 2022 Jun;8(6): e09575

Liposomes: An emerging carrier for targeting Alzheimer's and Parkinson's diseases.

Sureshbabu Ram Kumar Pandian, Kevin Kumar Vijayakumar, Sankaranarayanan Murugesan, Selvaraj Kunjiappan.

  The function of the brain can be affected by various factors that include infection, tumor, and stroke. The major disorders reported with altered brain function are Alzheimer's disease (AD), Parkinson's disease (PD), dementia, brain cancer, seizures, mental disorders, and other movement disorders. The major barrier in treating CNS disease is the blood-brain barrier (BBB), which protects the brain from toxic molecules, and the cerebrospinal fluid (CSF) barrier, which separates blood from CSF. Brain endothelial cells and perivascular elements provide an integrated cellular barrier, the BBB, which hamper the invasion of molecules from the blood to the brain. Even though many drugs are available to treat neurological disorders, it fails to reach the desired site with the required concentration. In this purview, liposomes can carry required concentrations of molecules intracellular by diverse routes such as carrier-mediated transport and receptor-mediated transcytosis. Surface modification of liposomes enables them to deliver drugs to various brain cells, including neurons, astrocytes, oligodendrocytes, and microglia. The research studies supported the role of liposomes in delivering drugs across BBB and in reducing the pathogenesis of AD and PD. The liposomes were surface-functionalized with various molecules to reach the cells intricated with the AD or PD pathogenesis. The targeted and sustained delivery of drugs by liposomes is disturbed due to the antibody formation, renal clearance, accelerated blood clearance, and complement activation-related pseudoallergy (CARPA). Hence, this review will focus on the characteristics, surface functionalization, drug loading, and biodistribution of liposomes respective to AD and PD. In addition, the alternative strategies to overcome immunogenicity are discussed briefly.

Keywords:  Alzheimer's disease; Blood-brain barrier; Brain; Delivery; Parkinson's disease

DOI:  https://doi.org/10.1016/j.heliyon.2022.e09575