bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2024–06–16
thirteen papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Lysosomal cholesterol accumulation in aged astrocytes impairs cholesterol delivery to neurons and can be rescued by cannabinoids.
  2. Spatial lipidomics maps brain alterations associated with mild traumatic brain injury.
  3. Mitochondrial membrane synthesis, remodelling and cellular trafficking.
  4. Brain metabolism after therapeutic hypothermia for murine hypoxia-ischemia using hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy.
  5. Glial metabolism versatility regulates mushroom body-driven behavioral output in Drosophila.
  6. The Spinocerebellar Ataxia 34-Causing W246G ELOVL4 Mutation Does Not Alter Cerebellar Neuron Populations in a Rat Model.
  7. Cerebral glucose metabolic correlates of cognitive and behavioural impairments in amyotrophic lateral sclerosis.
  8. Characterization of reduced astrocyte creatine kinase levels in Alzheimer's disease.
  9. Developmental pyrethroid exposure in mouse leads to disrupted brain metabolism in adulthood.
  10. SIRT3 facilitates mitochondrial structural repair and functional recovery in rats after ischemic stroke by promoting OPA1 expression and activity.
  11. APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling.
  12. The Gut-Brain Axis in Alzheimer's and Parkinson's Diseases: The Catalytic Role of Mitochondria.
  13. Non-transgenic guinea pig strains exhibit divergent age-related changes in hippocampal mitochondrial respiration.
  1. Glia. 2024 Jun 10.
    Lysosomal cholesterol accumulation in aged astrocytes impairs cholesterol delivery to neurons and can be rescued by cannabinoids.
    Leandro G Allende, Lautaro Natalí, Andrea B Cragnolini, Mariana Bollo, Melina M Musri, Diego de Mendoza, Mauricio G Martín.
      Cholesterol is crucial for the proper functioning of eukaryotic cells, especially neurons, which rely on cholesterol to maintain their complex structure and facilitate synaptic transmission. However, brain cells are isolated from peripheral cholesterol by the blood-brain barrier and mature neurons primarily uptake the cholesterol synthesized by astrocytes for proper function. This study aimed to investigate the effect of aging on cholesterol trafficking in astrocytes and its delivery to neurons. We found that aged astrocytes accumulated high levels of cholesterol in the lysosomal compartment, and this cholesterol buildup can be attributed to the simultaneous occurrence of two events: decreased levels of the ABCA1 transporter, which impairs ApoE-cholesterol export from astrocytes, and reduced expression of NPC1, which hinders cholesterol release from lysosomes. We show that these two events are accompanied by increased microR-33 in aged astrocytes, which targets ABCA1 and NPC1. In addition, we demonstrate that the microR-33 increase is triggered by oxidative stress, one of the hallmarks of aging. By coculture experiments, we show that cholesterol accumulation in astrocytes impairs the cholesterol delivery from astrocytes to neurons. Remarkably, we found that this altered transport of cholesterol could be alleviated through treatment with endocannabinoids as well as cannabidiol or CBD. Finally, according to data demonstrating that aged astrocytes develop an A1 phenotype, we found that cholesterol buildup is also observed in reactive C3+ astrocytes. Given that reduced neuronal cholesterol affects synaptic plasticity, the ability of cannabinoids to restore cholesterol transport from aged astrocytes to neurons holds significant implications in aging and inflammation.
    Keywords:  aging; astrocytes; cannabinoids; cholesterol; trafficking
    DOI:  https://doi.org/10.1002/glia.24580
  2. Front Chem. 2024 ;12 1394064
    Spatial lipidomics maps brain alterations associated with mild traumatic brain injury.
    Dmitry Leontyev, Alexis N Pulliam, Xin Ma, David A Gaul, Michelle C LaPlaca, Facundo M Fernández.
      Traumatic brain injury (TBI) is a global public health problem with 50-60 million incidents per year, most of which are considered mild (mTBI) and many of these repetitive (rmTBI). Despite their massive implications, the pathologies of mTBI and rmTBI are not fully understood, with a paucity of information on brain lipid dysregulation following mild injury event(s). To gain more insight on mTBI and rmTBI pathology, a non-targeted spatial lipidomics workflow utilizing high resolution mass spectrometry imaging was developed to map brain region-specific lipid alterations in rats following injury. Discriminant multivariate models were created for regions of interest including the hippocampus, cortex, and corpus callosum to pinpoint lipid species that differentiated between injured and sham animals. A multivariate model focused on the hippocampus region differentiated injured brain tissues with an area under the curve of 0.99 using only four lipid species. Lipid classes that were consistently discriminant included polyunsaturated fatty acid-containing phosphatidylcholines (PC), lysophosphatidylcholines (LPC), LPC-plasmalogens (LPC-P) and PC potassium adducts. Many of the polyunsaturated fatty acid-containing PC and LPC-P selected have never been previously reported as altered in mTBI. The observed lipid alterations indicate that neuroinflammation and oxidative stress are important pathologies that could serve to explain cognitive deficits associated with rmTBI. Therapeutics which target or attenuate these pathologies may be beneficial to limit persistent damage following a mild brain injury event.
    Keywords:  controlled cortical impact; fourier transform ion cyclotron resonance; mass spectrometry imaging; mild traumatic brain injury; spatial lipidomics
    DOI:  https://doi.org/10.3389/fchem.2024.1394064
  3. J Inherit Metab Dis. 2024 Jun 14.
    Mitochondrial membrane synthesis, remodelling and cellular trafficking.
    Martina Messina, Frédéric M Vaz, Shamima Rahman.
      Mitochondria are dynamic cellular organelles with complex roles in metabolism and signalling. Primary mitochondrial disorders are a group of approximately 400 monogenic disorders arising from pathogenic genetic variants impacting mitochondrial structure, ultrastructure and/or function. Amongst these disorders, defects of complex lipid biosynthesis, especially of the unique mitochondrial membrane lipid cardiolipin, and membrane biology are an emerging group characterised by clinical heterogeneity, but with recurrent features including cardiomyopathy, encephalopathy, neurodegeneration, neuropathy and 3-methylglutaconic aciduria. This review discusses lipid synthesis in the mitochondrial membrane, the mitochondrial contact site and cristae organising system (MICOS), mitochondrial dynamics and trafficking, and the disorders associated with defects of each of these processes. We highlight overlapping functions of proteins involved in lipid biosynthesis and protein import into the mitochondria, pointing to an overarching coordination and synchronisation of mitochondrial functions. This review also focuses on membrane interactions between mitochondria and other organelles, namely the endoplasmic reticulum, peroxisomes, lysosomes and lipid droplets. We signpost disorders of these membrane interactions that may explain the observation of secondary mitochondrial dysfunction in heterogeneous pathological processes. Disruption of these organellar interactions ultimately impairs cellular homeostasis and organismal health, highlighting the central role of mitochondria in human health and disease.
    Keywords:  MAM; MERC; MICOS; cardiolipin; cell trafficking; mitochondrial lipid biosynthesis; organellar crosstalk; primary mitochondrial disease
    DOI:  https://doi.org/10.1002/jimd.12766
  4. NMR Biomed. 2024 Jun 10. e5196
    Brain metabolism after therapeutic hypothermia for murine hypoxia-ischemia using hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy.
    Xiaodan Liu, Tiina Manninen, Alkisti Mikrogeorgiou Capper, Xiangning Jiang, Jacob Ellison, Yaewon Kim, Gokce Gurler, Duan Xu, Donna M Ferriero.
      Hypoxic-ischemic encephalopathy (HIE) is a common neurological syndrome in newborns with high mortality and morbidity. Therapeutic hypothermia (TH), which is standard of care for HIE, mitigates brain injury by suppressing anaerobic metabolism. However, more than 40% of HIE neonates have a poor outcome, even after TH. This study aims to provide metabolic biomarkers for predicting the outcomes of hypoxia-ischemia (HI) after TH using hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy. Postnatal day 10 (P10) mice with HI underwent TH at 1 h and were scanned at 6-8 h (P10), 24 h (P11), 7 days (P17), and 21 days (P31) post-HI on a 14.1-T NMR spectrometer. The metabolic images were collected, and the conversion rate from pyruvate to lactate and the ratio of lactate to pyruvate in the injured left hemisphere (kPL(L) and Lac/Pyr(L), respectively) were calculated at each timepoint. The outcomes of TH were determined by the assessments of brain injury on T2-weighted images and behavioral tests at later timepoint. kPL(L) and Lac/Pyr(L) over time between the good-outcome and poor-outcome groups and across timepoints within groups were analyzed. We found significant differences in temporal trends of kPL(L) and Lac/Pyr(L) between groups. In the good-outcome group, kPL(L) increased until P31 with a significantly higher value at P31 compared with that at P10, while the level of Lac/Pyr(L) at P31 was notably higher than those at all other timepoints. In the poor-outcome group, kPL(L) and Lac/Pyr(L) increased within 24 h. The kPL(L) value at P11 was considerably higher compared with P10. Discrete temporal changes of kPL(L) and Lac/Pyr(L) after TH between the good-outcome and poor-outcome groups were seen as early as 24 h after HI, reflecting various TH effects on brain anaerobic metabolism, which may provide insights for early screening for response to TH.
    Keywords:  anaerobic metabolism; hyperpolarized [1‐13C] pyruvate MR spectroscopy; hypoxic‐ischemic encephalopathy; therapeutic hypothermia
    DOI:  https://doi.org/10.1002/nbm.5196
  5. Learn Mem. 2024 May;pii: a053823. [Epub ahead of print]31(5):
    Glial metabolism versatility regulates mushroom body-driven behavioral output in Drosophila.
    Ruchira Basu, Thomas Preat, Pierre-Yves Plaçais.
      Providing metabolic support to neurons is now recognized as a major function of glial cells that is conserved from invertebrates to vertebrates. However, research in this field has focused for more than two decades on the relevance of lactate and glial glycolysis for neuronal energy metabolism, while overlooking many other facets of glial metabolism and their impact on neuronal physiology, circuit activity, and behavior. Here, we review recent work that has unveiled new features of glial metabolism, especially in Drosophila, in the modulation of behavioral traits involving the mushroom bodies (MBs). These recent findings reveal that spatially and biochemically distinct modes of glucose-derived neuronal fueling are implemented within the MB in a memory type-specific manner. In addition, cortex glia are endowed with several antioxidant functions, whereas astrocytes can serve as pro-oxidant agents that are beneficial to redox signaling underlying long-term memory. Finally, glial fatty acid oxidation seems to play a dual fail-safe role: first, as a mode of energy production upon glucose shortage, and, second, as a factor underlying the clearance of excessive oxidative load during sleep. Altogether, these integrated studies performed in Drosophila indicate that glial metabolism has a deterministic role on behavior.
    DOI:  https://doi.org/10.1101/lm.053823.123
  6. Cerebellum. 2024 Jun 08.
    The Spinocerebellar Ataxia 34-Causing W246G ELOVL4 Mutation Does Not Alter Cerebellar Neuron Populations in a Rat Model.
    Jennifer L Fessler, Megan A Stiles, Martin-Paul Agbaga, Mohiuddin Ahmad, David M Sherry.
      Spinocerebellar ataxia 34 (SCA34) is an autosomal dominant disease that arises from point mutations in the fatty acid elongase, Elongation of Very Long Chain Fatty Acids 4 (ELOVL4), which is essential for the synthesis of Very Long Chain-Saturated Fatty Acids (VLC-SFA) and Very Long Chain-Polyunsaturated Fatty Acids (VLC-PUFA) (28-34 carbons long). SCA34 is considered a neurodegenerative disease. However, a novel rat model of SCA34 (SCA34-KI rat) with knock-in of the W246G ELOVL4 mutation that causes human SCA34 shows early motor impairment and aberrant synaptic transmission and plasticity without overt neurodegeneration. ELOVL4 is expressed in neurogenic regions of the developing brain, is implicated in cell cycle regulation, and ELOVL4 mutations that cause neuroichthyosis lead to developmental brain malformation, suggesting that aberrant neuron generation due to ELOVL4 mutations might contribute to SCA34. To test whether W246G ELOVL4 altered neuronal generation or survival in the cerebellum, we compared the numbers of Purkinje cells, unipolar brush cells, molecular layer interneurons, granule and displaced granule cells in the cerebellum of wildtype, heterozygous, and homozygous SCA34-KI rats at four months of age, when motor impairment is already present. An unbiased, semi-automated method based on Cellpose 2.0 and ImageJ was used to quantify neuronal populations in cerebellar sections immunolabeled for known neuron-specific markers. Neuronal populations and cortical structure were unaffected by the W246G ELOVL4 mutation by four months of age, a time when synaptic and motor dysfunction are already present, suggesting that SCA34 pathology originates from synaptic dysfunction due to VLC-SFA deficiency, rather than aberrant neuronal production or neurodegeneration.
    Keywords:  Granule cell; Molecular layer interneuron; Neurodegeneration; Neurodevelopment; Purkinje cell; SCA34; Unipolar brush cell
    DOI:  https://doi.org/10.1007/s12311-024-01708-8
  7. J Neurol. 2024 Jun 11.
    Cerebral glucose metabolic correlates of cognitive and behavioural impairments in amyotrophic lateral sclerosis.
    Annaliis Lehto, Julia Schumacher, Elisabeth Kasper, Stefan Teipel, Andreas Hermann, Jens Kurth, Bernd Joachim Krause, Johannes Prudlo.
       OBJECTIVE: Half of ALS patients are cognitively and/or behaviourally impaired. As cognition/behaviour and cerebral glucose metabolism can be correlated by means of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET), we aimed to utilise FDG-PET, first, to replicate group-level differences in glucose metabolism between non-demented ALS patients separated into non-impaired (ALSni), cognitively impaired (ALSci), behaviourally impaired (ALSbi), and cognitively and behaviourally impaired (ALScbi) groups; second, to investigate glucose metabolism and performance in various cognitive domains; and third, to examine the impact of partial volume effects correction (PVEC) of the FDG-PET data on the results.
    METHODS: We analysed neuropsychological, clinical, and imaging data from 67 ALS patients (30 ALSni, 21 ALSci, 5 ALSbi, and 11 ALScbi). Cognition was assessed with the Edinburgh Cognitive and Behavioural ALS Screen, and two social cognition tests. FDG-PET and structural MRI scans were acquired for each patient. Voxel-based statistical analyses were undertaken on grey matter volume (GMV) and non-corrected vs. PVE-corrected FDG-PET scans.
    RESULTS: ALSci and ALScbi had lower cognitive scores than ALSni. In contrast to both ALSni and ALSci, ALScbi showed widespread hypometabolism in the superior- and middle-frontal gyri in addition to the right temporal pole. Correlations were observed between the GMV, the FDG-PET signal, and various cognitive scores. The FDG-PET results were largely unaffected by PVEC.
    INTERPRETATION: Our study identified widespread differences in hypometabolism in the ALScbi-ni but not in the ALSci-ni group comparison, raising the possibility that cerebral metabolism may be more closely related to the presence of behavioural changes than to mild cognitive deficits.
    Keywords:  Amyotrophic lateral sclerosis; Cerebral glucose metabolism; Cognition; FDG-PET; Grey matter volume
    DOI:  https://doi.org/10.1007/s00415-024-12388-z
  8. Glia. 2024 Jun 10.
    Characterization of reduced astrocyte creatine kinase levels in Alzheimer's disease.
    Tianyu Zheng, David Kotol, Rebecca Sjöberg, Nicholas Mitsios, Mathias Uhlén, Wen Zhong, Fredrik Edfors, Jan Mulder.
      The creatine-phosphocreatine cycle serves as a crucial temporary energy buffering system in the brain, regulated by brain creatine kinase (CKB), in maintaining Adenosine triphosphate (ATP) levels. Alzheimer's disease (AD) has been linked to increased CKB oxidation and loss of its regulatory function, although specific pathological processes and affected cell types remain unclear. In our study, cerebral cortex samples from individuals with AD, dementia with Lewy bodies (DLB), and age-matched controls were analyzed using antibody-based methods to quantify CKB levels and assess alterations associated with disease processes. Two independently validated antibodies exclusively labeled astrocytes in the human cerebral cortex. Combining immunofluorescence (IF) and mass spectrometry (MS), we explored CKB availability in AD and DLB cases. IF and Western blot analysis demonstrated a loss of CKB immunoreactivity correlated with increased plaque load, severity of tau pathology, and Lewy body pathology. However, transcriptomics data and targeted MS demonstrated unaltered total CKB levels, suggesting posttranslational modifications (PTMs) affecting antibody binding. This aligns with altered efficiency at proteolytic cleavage sites indicated in the targeted MS experiment. These findings highlight that the proper function of astrocytes, understudied in the brain compared with neurons, is highly affected by PTMs. Reduction in ATP levels within astrocytes can disrupt ATP-dependent processes, such as the glutamate-glutamine cycle. As CKB and the creatine-phosphocreatine cycle are important in securing constant ATP availability, PTMs in CKB, and astrocyte dysfunction may disturb homeostasis, driving excitotoxicity in the AD brain. CKB and its activity could be promising biomarkers for monitoring early-stage energy deficits in AD.
    Keywords:  brain creatine kinase; dementia with Lewy bodies; multiplex immunofluorescence; targeted mass spectrometry; temporal cortex
    DOI:  https://doi.org/10.1002/glia.24569
  9. Neurotoxicology. 2024 Jun 12. pii: S0161-813X(24)00063-9. [Epub ahead of print]
    Developmental pyrethroid exposure in mouse leads to disrupted brain metabolism in adulthood.
    Melissa A Curtis, Nilanjana Saferin, Jennifer H Nguyen, Ali S Imami, William G Ryan, Kari L Neifer, Gary W Miller, James P Burkett.
      Environmental and genetic risk factors, and their interactions, contribute significantly to the etiology of neurodevelopmental disorders (NDDs). Recent epidemiology studies have implicated pyrethroid pesticides as an environmental risk factor for autism and developmental delay. Our previous research showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin in mice caused male-biased changes in the brain and in NDD-relevant behaviors in adulthood. Here, we used a metabolomics approach to determine the broadest possible set of metabolic changes in the adult male mouse brain caused by low-dose pyrethroid exposure during development. Using a litter-based design, we exposed mouse dams during pregnancy and lactation to deltamethrin (3mg/kg or vehicle every 3 days) at a concentration well below the EPA-determined benchmark dose used for regulatory guidance. We raised male offspring to adulthood and collected whole brain samples for untargeted high-resolution metabolomics analysis. Developmentally exposed mice had disruptions in 116 metabolites which clustered into pathways for folate biosynthesis, retinol metabolism, and tryptophan metabolism. As a cross-validation, we integrated metabolomics and transcriptomics data from the same samples, which confirmed previous findings of altered dopamine signaling. These results suggest that pyrethroid exposure during development leads to disruptions in metabolism in the adult brain, which may inform both prevention and therapeutic strategies.
    Keywords:  brain; developmental exposure; metabolomics; pyrethroids
    DOI:  https://doi.org/10.1016/j.neuro.2024.06.007
  10. Clin Nutr. 2024 Jun 06. pii: S0261-5614(24)00193-6. [Epub ahead of print]43(7): 1816-1831
    SIRT3 facilitates mitochondrial structural repair and functional recovery in rats after ischemic stroke by promoting OPA1 expression and activity.
    Hongbin Chen, Ji Liu, Manli Chen, Zengyu Wei, Jinjin Yuan, Wenwen Wu, Zhiyun Wu, Zhijian Zheng, Zijun Zhao, Qiang Lin, Nan Liu.
       BACKGROUND: Optical atrophy 1 (OPA1), a protein accountable for mitochondrial fusion, facilitates the restoration of mitochondrial structure and function following cerebral ischemia/reperfusion (I/R) injury. The OPA1-conferred mitochondrial protection involves its expression and activity, which can be improved by SIRT3 in non-cerebral ischemia. Nevertheless, it remains obscure whether SIRT3 enhances the expression and activity of OPA1 after cerebral I/R injury.
    METHODS: Mature male Sprague Dawley rats were intracranially injected with adeno-associated viral-Sirtuin-3(AAV-SIRT3) and AAV-sh_OPA1, followed by a 90-min temporary blockage of the middle cerebral artery and subsequent restoration of blood flow. Cultured cortical neurons of rats were transfected with LV-SIRT3 or LV-sh_OPA1 before a 2-h oxygen-glucose deprivation and reoxygenation. The rats and neurons were subsequently treated with a selective OPA1 activity inhibitor (MYLS22). The interaction between SIRT3 and OPA1 was assessed by molecular dynamics simulation technology and co-immunoprecipitation. The expression, function, and specific protective mechanism of SIRT3 were examined by various analyses.
    RESULTS: SIRT3 interacted with OPA1 in the rat cerebral cortex before and after cerebral I/R. After cerebral I/R damage, SIRT3 upregulation increased the OPA1 expression, which enhanced deacetylation and OPA1 activity, thus alleviating cerebral infarct volume, neuronal apoptosis, oxidative pressure, and impairment in mitochondrial energy production; SIRT3 upregulation also improved neuromotor performance, repaired mitochondrial ultrastructure and membrane composition, and promoted the mitochondrial biogenesis. These neuroprotective effects were partly reversed by OPA1 expression interference and OPA1 activity inhibitor MYLS22.
    CONCLUSION: In rats, SIRT3 enhances the expression and activity of OPA1, facilitating the repair of mitochondrial structure and functional recovery following cerebral I/R injury. These findings highlight that regulating SIRT3 may be a promising therapeutic strategy for ischemic stroke.
    Keywords:  Cerebral ischemia/reperfusion injury; Mitochondrion; OPA1; Oxidative stress; SIRT3
    DOI:  https://doi.org/10.1016/j.clnu.2024.06.001
  11. Cell Mol Biol Lett. 2024 Jun 12. 29(1): 87
    APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling.
    Zhiyuan Ning, Ying Liu, Mengyao Wan, You Zuo, Siqi Chen, Zhongshan Shi, Yongteng Xu, Honghong Li, Ho Ko, Jing Zhang, Songhua Xiao, Daji Guo, Yamei Tang.
       BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear.
    METHODS: We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively.
    RESULTS: The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aβ). Moreover, APOE2 overexpression alleviates Aβ1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aβ1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aβ injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice.
    CONCLUSIONS: APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.
    Keywords:  Alzheimer's disease; Apolipoprotein E; Beta-amyloid (Aβ); ESRRA; Mitochondria; Neuron
    DOI:  https://doi.org/10.1186/s11658-024-00600-x
  12. J Alzheimers Dis. 2024 Jun 08.
    The Gut-Brain Axis in Alzheimer's and Parkinson's Diseases: The Catalytic Role of Mitochondria.
    Emanuel Candeias, Ana Raquel Pereira-Santos, Nuno Empadinhas, Sandra Morais Cardoso, Ana Raquel Fernandes Esteves.
      Accumulating evidence suggests that gut inflammation is implicated in neuroinflammation in Alzheimer's and Parkinson's disease. Despite the numerous connections it remains unclear how the gut and the brain communicate and whether gut dysbiosis is the cause or consequence of these pathologies. Importantly, several reports highlight the importance of mitochondria in the gut-brain axis, as well as in mechanisms like gut epithelium self-renewal, differentiation, and homeostasis. Herein we comprehensively address the important role of mitochondria as a cellular hub in infection and inflammation and as a link between inflammation and neurodegeneration in the gut-brain axis. The role of mitochondria in gut homeostasis and as well the crosstalk between mitochondria and gut microbiota is discussed. Significantly, we also review studies highlighting how gut microbiota can ultimately affect the central nervous system. Overall, this review summarizes novel findings regarding this cross-talk where the mitochondria has a main role in the pathophysiology of both Alzheimer's and Parkinson's disease strengthen by cellular, animal and clinical studies.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; gut microbiome metabolites; gut-brain axis; inflammation; mitochondria
    DOI:  https://doi.org/10.3233/JAD-240524
  13. Acta Physiol (Oxf). 2024 Jun 11. e14185
    Non-transgenic guinea pig strains exhibit divergent age-related changes in hippocampal mitochondrial respiration.
    Maureen A Walsh, Amanda S Latham, Qian Zhang, Robert A Jacobs, Robert V Musci, Thomas J LaRocca, Julie A Moreno, Kelly S Santangelo, Karyn L Hamilton.
       AIM: Alzheimer's disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi-morbidities of human aging. We previously demonstrated that, in comparison to the PigmEnTed (PET) guinea pig strain which models "typical" brain aging, the Hartley strain develops hallmarks of AD like aging humans. Hartleys also exhibit age-related impairments in cartilage and skeletal muscle. Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age-related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain.
    METHODS: Therefore, we assessed hippocampal mitochondrial respiration in 5- and 12-month Hartley and PET guinea pigs using high-resolution respirometry.
    RESULTS: At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age.
    CONCLUSIONS: Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression.
    Keywords:  brain aging; guinea pig; hippocampus; mitochondrial respiration; non‐transgenic
    DOI:  https://doi.org/10.1111/apha.14185
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