Diet Restriction Slows Neurodegeneration and Extends Lifespan of DNA-Repair-Deficient Mice

DNA damage occurs in human cells at a constant rate. These cells are usually able to repair themselves, but sometimes deficiencies in certain genes cause the repair process to shut down. When damaged DNA isn’t fixed, mutations can occur that cause accelerated aging or cancerous tumors to form (Hoeijmakers, 2009). Scientists at Erasmus University Medical Center in Rotterdam have found a way to slow down the process – at least in mice.

In a study published in Nature, the researchers report that when mice deficient in the DNA-repair genes Ercc1 or Xpg are put on a restricted diet, they experience better overall health and increased lifespans compared to DNA-repair-deficient mice fed a normal diet. They also found significantly lower levels of neurodegeneration in the brains and spinal cords of diet restricted animals compared to controls.

“Here we report that a dietary restriction of 30 percent tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated aging Mice undergoing dietary restriction retained 50 percent more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum,” (Vermeij, et al 2016).

Since the DNA-repair-deficient mice were already smaller and weaker than normal mice, the Rotterdam researchers wondered whether diet restriction would be beneficial or detrimental to their health. They found that gradually restricting the diets of DNA-repair-deficient mice starting at age seven weeks increased their median lifespans from 10 to 35 weeks in males and 13 to 39 weeks in females as compared to controls.

They also saw significant differences in the levels of neurodegeneration between these two populations. Using Stereo Investigator, they found 50 percent more neurons in the brains of diet-restricted mice compared to those fed a normal diet. They also saw lower levels of cells expressing p53 – a protein expressed in response to DNA damage – in diet-restricted mice.

According to the authors, dietary restriction may not fix defects in DNA repair mechanisms, but it may help to reduce the severity and speed at which the damage occurs.

“Our findings establish the Ercc1 mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general,” (Vermeij, et al 2016).

Vermeij W.P., Dollé M.E.T., Reiling E., Jaarsma D., Payan-Gomez C, Bombardieri C.R., Wu H., Roks A.J.M., Botter S.M., van der Eerden B.C., Youssef S.A., Kuiper R.V., Nagarajah B., van Oostrom C.T., Brandt R.M.C., Barnhoorn S., Imholz S., Pennings J.L.A., de Bruin A., Gyenis Á., Pothof J, Vijg J, van Steeg H., and Hoeijmakers J.H.J. (2016) Restricted diet delays accelerated aging and genomic stress in DNA repair deficient mice. Nature 537, 427-431, doi:10.1038/nature19329

Hoeijmakers JH (2009) DNA Damage, aging, and cancer. N Engl J Med; 361:1475-1485, DOI: 10.1056/NEJMra0804615

Stock image of DNA used in accordance with the CC0 public domain license.

Researchers cited MBF systems in 29 papers between 6/30/2017 to 7/14/2017

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Abdurakhmanova, S., Chary, K., Kettunen, M., Sierra, A., & Panula, P. (2017). Behavioral and stereological characterization of Hdc KO mice: relation to Tourette syndrome. Journal of Comparative Neurology, n/a-n/a. doi: 10.1002/cne.24279.

Arathoon, L. R., Gleave, J. A., Trinh, D., Lizal, K. E., Giguère, N., Barber, J. H. M., . . . Nash, J. E. (2017). Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism. Neurobiology of Disease. doi: https://doi.org/10.1016/j.nbd.2017.06.009.

Chen, L., Wang, X., Lin, Z.-X., Dai, J.-G., Huang, Y.-F., & Zhao, Y.-N. (2017). Preventive Effects of Ginseng Total Saponins on Chronic Corticosterone-Induced Impairment in Astrocyte Structural Plasticity and Hippocampal Atrophy. Phytotherapy Research, n/a-n/a. doi: 10.1002/ptr.5859.

Collette, J. C., Choubey, L., & Smith, K. M. (2017). ­Glial and stem cell expression of murine Fibroblast Growth Factor Receptor 1 in the embryonic and perinatal nervous system. PeerJ, 5, e3519. doi: 10.7717/peerj.3519.

Filice, F., Celio, M. R., Babalian, A., Blum, W., & Szabolcsi, V. (2017). Parvalbumin-expressing ependymal cells in rostral lateral ventricle wall adhesions contribute to aging-related ventricle stenosis in mice. Journal of Comparative Neurology, n/a-n/a. doi: 10.1002/cne.24276.

Finkelstein, D. I., Billings, J. L., Adlard, P. A., Ayton, S., Sedjahtera, A., Masters, C. L., . . . Cherny, R. A. (2017). The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease. Acta Neuropathologica Communications, 5(1), 53. doi: 10.1186/s40478-017-0456-2.

Han, S.-W., Kim, Y.-C., & Narayanan, N. S. (2017). Projection targets of medial frontal D1DR-expressing neurons. Neuroscience Letters. doi: http://dx.doi.org/10.1016/j.neulet.2017.06.057.

Lee, J. Q., Sutherland, R. J., & McDonald, R. J. (2017). Hippocampal damage causes retrograde but not anterograde memory loss for context fear discrimination in rats. Hippocampus, n/a-n/a. doi: 10.1002/hipo.22759.

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Researchers cited MBF systems in 25 papers between 5/16/2017 and 5/26/2017

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Baxter, V. K., Glowinski, R., Braxton, A. M., Potter, M. C., Slusher, B. S., & Griffin, D. E. (2017). Glutamine antagonist-mediated immune suppression decreases pathology but delays virus clearance in mice during nonfatal alphavirus encephalomyelitis. Virology, 508, 134-149. doi: https://doi.org/10.1016/j.virol.2017.05.013.

Brzozowska, N. I., Smith, K. L., Zhou, C., Waters, P. M., Cavalcante, L. M., Abelev, S. V., . . . Arnold, J. C. (2017). Genetic deletion of P-glycoprotein alters stress responsivity and increases depression-like behavior, social withdrawal and microglial activation in the hippocampus of female mice. Brain, Behavior, and Immunity. doi: https://doi.org/10.1016/j.bbi.2017.05.008.

Chareyron, L. J., Banta Lavenex, P., Amaral, D. G., & Lavenex, P. (2017). Functional organization of the medial temporal lobe memory system following neonatal hippocampal lesion in rhesus monkeys. Brain Structure and Function, 1-16. doi: 10.1007/s00429-017-1441-z.

Kwan, T., Floyd, C. L., Patel, J., Mohaimany-Aponte, A., & King, P. H. (2017). Astrocytic expression of the RNA regulator HuR accentuates spinal cord injury in the acute phase. Neuroscience Letters, 651, 140-145. doi: https://doi.org/10.1016/j.neulet.2017.05.003.

Newville, J., Valenzuela, C. F., Li, L., Jantzie, L. L., & Cunningham, L. A. (2017). Acute oligodendrocyte loss with persistent white matter injury in a third trimester equivalent mouse model of fetal alcohol spectrum disorder. Glia, n/a-n/a. doi: 10.1002/glia.23164.

Onger, M. E., Kaplan, S., Geuna, S., Türkmen, A. P., Muratori, L., Altun, G., & Altunkaynak, B. Z. (2017). Possible effects of some agents on the injured nerve in obese rats: A stereological and electron microscopic study. Journal of Cranio-Maxillofacial Surgery. doi: https://doi.org/10.1016/j.jcms.2017.05.004.

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Uncovering the role of microglia in fetal alcohol spectrum disorders

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Representative images of Iba-1+ microglia in the postnatal day 10 rat hippocampus. Image courtesy of Anna Klintsova, PhD.

Children born with fetal alcohol spectrum disorders face a range of physical and cognitive impairments including long-term deficits in learning, behavior, and immune function. In a paper published in Neuroscience, Dr. Anna Klintsova and her lab at the University of Delaware report that activation of the brain’s immune response may contribute to some of the damage caused by fetal alcohol spectrum disorders.

In their study, the researchers used Stereo Investigator and Neurolucida to examine the hypothesis that exposure to alcohol while the brain is growing rapidly is associated with abnormal microglial activation and high levels of pro-inflammatory proteins which impair learning-related plasticity; leading to neuro-developmental and psychopathological disorders.

“My lab has been using both Stereo Investigator and Neurolucida for more than a decade in all quantitative neuroanatomical studies, including the featured one,” said Dr. Anna Klintsova. “We find this software to be user-friendly, reliable and essential for obtaining unbiased results.”

They used Stereo Investigator to quantify the number of microglia in the hippocampus of neonatal rats who were exposed to alcohol during the equivalent of the third trimester of a human pregnancy. The researchers expected to see an increased number of microglia in alcohol-exposed neonatal rats, however they found a decreased number of microglia. Despite the decrease in microglia number, there was a significant increase in pro-inflammatory proteins expressed by microglia and an increase in microglial activation.

To measure microglial activation, the researchers quantified the area of cell territory using Neurolucida. Activated microglia have a smaller cell territory than resting microglia, so the smaller cell territory found in alcohol exposed rats indicates a more active state.

This research supports the hypothesis that abnormal microglia activation plays a role in fetal alcohol spectrum disorders, however more research is needed to further understand the relationship.

Boschen, K., Ruggiero, M.J., Klintsova, A.Y., (2016) Neonatal binge alcohol exposure increases microglial activation in the developing rat hippocampus. Neuroscience 324: 355–366. DOI: 10.1016/j.neuroscience.2016.03.033

 

Stereological Study Reveals Neuron and Glia Proliferation in Hippocampus of Lithium-Treated Mice

Dentate gyruspilot

The optical fractionator probe was used to quantify the number of neurons and glia in the dentate gyrus

Doctors have used lithium to treat patients with bipolar disorder since the 1970s. Known for its efficacy in stabilizing patients’ moods by regulating manic episodes, lithium is also associated with a decreased risk of suicide. But while this naturally occurring element is the most widely prescribed medication for those suffering from bipolar disorder, scientists still have much to learn about how lithium physically affects the brain.

A recent study published in the journal Bipolar Disorders adds to the growing body of evidence that says lithium contributes to cell proliferation in parts of the brain. Conducted by scientists at the University of Mississippi and the VU University Medical Center in Amsterdam, the study revealed an increased number of neurons and glia, and increased astrocyte density in the dentate gyrus of lithium-treated mice versus controls treated with a placebo.

Using the optical fractionator probe in Stereo Investigator, the researchers quantified the number of Nissl stained neurons and glial cells, and calculated astrocyte density. The results showed twenty-five percent more neurons and twenty-one percent more glia in the denate gyrus of lithium-treated mice. They also performed a stereological examination of another brain region – the medial prefrontal cortex (mPFC), but did not witness significant differences between lithium-treated and control mice in this area.

“In this study, particular cortical regions, ie. the fascia dentata in the hippocampus and the mPFC in the cerebral cortex needed to be selected in histological sections of the mice brains,” explained Dr. Harry B.M. Uylings, “therefore the stereological counting procedure applied was the best one. Stereo Investigator greatly assisted in the counting of cells, and the software’s excel data-output was especially beneficial.”

According to the paper, the findings present a more detailed picture of lithium-induced alterations in the dentate gyrus cellular phenotype than previously available, and provide the first evidence for lithium-induced increases in glia and astrocytes.

The authors also explain that while cell number increased in the dentate gyrus of lithium-treated mice, the region’s overall volume as well as that of the greater hippocampus was unaffected by the element. The volume of the dentate gyrus and the hippocampus as a whole was measured with the Cavalieri method in Stereo Investigator.  The researchers describe the dissociation between cell proliferation and volume as “an interesting observation that warrants further investigation.”

Rajkowska, G., Clarke, G., Mahajan, G., Licht, C.M., van de Werd, H.J., Yuan, P., Stockmeier, C.A., Maji, H.K., Uylings, H.B., Differential effect of lithium on cell number in the hippocampus and prefrontal cortex in adult mice: a stereological study. Bipolar Disord. 2016 Feb;18(1):41-51. doi: 10.1111/bdi.12364.

Iron Deficiency Worsens Fetal Alcohol Spectrum Disorders

An immunostained image of myelin basic protein in the cerebella of a mouse brain with an iron-sufficient diet compared with the brain of a mouse exposed to alcohol and fed an iron-insufficient diet. It shows the reduced cerebellar size due to the ID-alcohol combination. Green is MBP immunostain, blue is DAPI for nuclei.

An immunostained image of myelin basic protein in the cerebella of a mouse brain with an iron-sufficient diet compared with the brain of a mouse exposed to alcohol and fed an iron-insufficient diet. It shows the reduced cerebellar size due to the ID-alcohol combination. Green is MBP immunostain, blue is DAPI for nuclei. Image courtesy of Susan Smith, PhD.

If a pregnant woman drinks alcohol, she risks giving birth to a baby with physical and cognitive deficits – characteristics of fetal alcohol spectrum disorders. In a new study, researchers say that when the mother is low in iron, the consequences are even worse.

The scientists examined two groups of pregnant rats – one group was fed an iron sufficient diet while the other was fed a diet with insufficient iron levels. The offspring from both groups were exposed to alcohol from 4 to 9 days after birth – a time when their brains are going through a growth spurt and are particularly sensitive to alcohol. They were compared to offspring who received an iron-sufficient diet but were not exposed to alcohol. This growth spurt correlates to a growth spurt in humans that occurs during the third trimester of pregnancy.

The researchers used delay and trace eye blink classical conditioning methods to assess the offspring’s learning and memory. Learning impairments were reported in both alcohol-exposed groups regardless of their iron status, but more extreme impairments were seen in iron deficient rats compared to iron sufficient rats. After the behavioral tests were completed, the researchers studied the cerebellum and hippocampus – brain regions involved in learning and memory – at a cellular level.

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Genetic Mutation Accelerates CTE Pathology

Phosphorylated tau pS422 immunoreactive profiles in the cortex of P301Smice after repetitive mild TBI. Image courtesy of Dr. Leyan Xu.

Phosphorylated tau pS422 immunoreactive profiles (dark brown) in the cortex of P301S mice after repetitive mild TBI. Image courtesy of Dr. Leyan Xu, Department of Pathology, Johns Hopkins University.

Over the course of a football game or a boxing match, athletes may experience a series of mild concussions. Some of these athletes develop a condition known as chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by the build-up of abnormal tau protein that eventually leads to dementia. But not every athlete develops CTE after repetitive mild traumatic brain injury, and scientists think genetic factors are involved.

In a recent study, researchers at the Johns Hopkins University School of Medicine found that the density of abnormal tau protein increased exponentially in mice that had a genetic mutation thought to cause neurodegenerative diseases. Their findings contrast with previous studies of mice without genetic mutation, where abnormal tau protein build-up did not occur. This evidence leads the scientists to infer that genetic factors play a role in the onset of CTE.

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Researchers cited MBF systems in 24 papers between 11/2/2015 and 11/13/2015

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Bains, M., & Roberts, J. L. (2015). Estrogen protects against dopamine neuron toxicity in primary mesencephalic cultures through an indirect P13K/Akt mediated astrocyte pathway. Neuroscience Letters. doi:http://dx.doi.org/10.1016/j.neulet.2015.10.054.

Chen, M.-h., Liu, Y.-h., Xu, H., Xu, D.-w., Wang, C.-n., Wang, Y., . . . Wang, Y.-h. (2015). Lentiviral Vector-Mediated p27kip1 Expression Facilitates Recovery After Spinal Cord Injury. Molecular Neurobiology, 1-14. doi: 10.1007/s12035-015-9498-2.

Correa, M., Pardo, M., Bayarri, P., López-Cruz, L., San Miguel, N., Valverde, O., . . . Salamone, J. (2015). Choosing voluntary exercise over sucrose consumption depends upon dopamine transmission: effects of haloperidol in wild type and adenosine A2AKO mice. Psychopharmacology, 1-12. doi: 10.1007/s00213-015-4127-3.

Fragale, J. E. C., Khariv, V., Gregor, D. M., Smith, I. M., Jiao, X., Elkabes, S., . . . Beck, K. D. (2016). Dysfunction in amygdala–prefrontal plasticity and extinction-resistant avoidance: A model for anxiety disorder vulnerability. Experimental Neurology, 275, Part 3, 59-68. doi:http://dx.doi.org/10.1016/j.expneurol.2015.11.002.

Goodus, M. T., Kerr, N. A., Talwar, R., Buziashvili, D., Fragale, J. E. C., Pang, K., & Levison, S. W. (2015). LIF Haplodeficiency Desynchronizes Glial Reactivity and Exacerbates Damage and Functional Deficits After a Concussive Brain Injury. Journal of Neurotrauma. doi: 10.1089/neu.2015.4234.

Huang, Q., Du, X., He, X., Yu, Q., Hu, K., Breitwieser, W., . . . Li, M. (2015). JNK-mediated activation of ATF2 contributes to dopaminergic neurodegeneration in the MPTP mouse model of Parkinson’s disease. Experimental Neurology. doi: http://dx.doi.org/10.1016/j.expneurol.2015.10.010.

Jayasinghe, V. R., Flores-Barrera, E., West, A. R., & Tseng, K. Y. (2015). Frequency-Dependent Corticostriatal Disinhibition Resulting from Chronic Dopamine Depletion: Role of Local Striatal cGMP and GABA-AR Signaling. Cerebral Cortex. doi: 10.1093/cercor/bhv241.

Kohl, Z., Abdallah, N. B., Vogelgsang, J., Tischer, L., Deusser, J., Amato, D., . . . Winkler, J. (2015). Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC α-synuclein transgenic rat model of Parkinson’s disease. Neurobiology of Disease. doi:http://dx.doi.org/10.1016/j.nbd.2015.10.021.

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Dying neurons in Alzheimer’s patients show signs of improvement after gene therapy

nucleus basalis of Meynert

Micrograph of cholinergic neurons in the nucleus basalis of Meynert. Image from Wikipedia.

 

Cholinergic neurons degenerate at devastating rates in Alzheimer’s disease, but Dr. Mark Tuszynski and his team at the University of California, San Diego may have found a way to slow the decline.

Their study, published in JAMA Neurology, reports that nerve growth factor gene therapy increased the size, axonal sprouting, and signaling of cholinergic neurons in 10 Alzheimer’s disease patients.

The patients were enrolled in a clinical trial between 2001 and 2012. Ex vivo and in vivo methods of gene therapy were used to deliver nerve growth factor – a protein that protects neurons and stimulates growth – to the patients. Eight received an implant of their own skin cells that were genetically modified to express nerve growth factor (ex vivo ) and two patients received injections that induced neurons already in the brain to express nerve growth factor (in vivo). In all 10 patients, gene therapy was delivered to the nucleus basalis of Meynert – part of the basal forebrain rich in cholinergic neurons that undergoes degeneration during Alzheimer’s disease. 

The patients’ survival time ranged from one to 10 years. After they had died, researchers analyzed the effects of nerve growth factor on cholinergic neurons.

The axons of cholinergic neurons, labeled with p75, grew toward the source of the nerve growth factor in all 10 patients. To determine if there was a change in cell size, researchers used the nucleator probe in Stereo Investigator to analyze cholinergic neurons of 3 patients who received gene therapy via the ex vivo method in one hemisphere – the other hemisphere was used as a control. Results from Stereo Investigator showed that cell bodies were larger in the treated hemisphere vs. the untreated hemisphere.

Finally, to find out if nerve growth factor induced signaling within cells, the researchers analyzed the amount of CREB and c-fos – markers for cell activation – in 2 patients who received nerve growth factor in vivo. An elevated amount of CREB and c-fos was found when compared to control regions. Neurons exhibiting tau pathology also expressed nerve growth factor, indicating that degenerating cells could respond to nerve growth factor gene therapy.

A phase 2 clinical study is currently under way to report cognitive outcomes in patients with Alzheimer’s disease.

“Collectively, these anatomical findings support the rationale for clinical trials to test the hypothesis that sustained growth factor delivery over time can reduce cell degeneration and stimulate cell function in chronic neurodegenerative disorders, thereby slowing functional decline,” Tuszynski, et al.

Tuszynski, M.H., Yang, J.H., Pay, M.M., Masliah, E., Barba, D., U, H.S., Conner, J.M., Kobalka, P., Roy, S., and Nagahara A.H. (2015). Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurology, published online August 24, 2015. DOI: 10.1001/jamaneurol.2015.1807.

Researchers Explore Spatial Memory with Stereo Investigator

The researchers quantified c-Fos positive cells in the CA1 region of the hippocampus. Image provided by Dr. Matthew Holahan.

The researchers quantified c-Fos positive cells in the CA1 region of the hippocampus. Image provided by Dr. Matthew Holahan.

Spacial memories help us navigate places like the office, the local coffee shop, or the supermarket. The hippocampus plays a key role in processing and recalling spacial memory, but as time passes, there is evidence that the anterior cingulate cortex (ACC) becomes more involved in recalling these memories. A recent paper published in PLOS ONE further investigates the ACC and found that taxing the hippocampus with spacial memory tasks accelerates the recruitment of the ACC for spacial memory recall.

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