Complement-cascade and Alzheimer

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The question the essay is going to answer is:

“What are the pathways (focus on proteins (c1q and c3)) should be considered for future medication for the neurodegenerative disease (mostly Alzheimer)?”

You should incorporate evidence from the (list of articles given below) in to your report (no need to use all of them only the ones that can relate to the answer of the question above).

You could discuss potential future drug targets based on the specific molecular-cellular pathways, you should also think about the caveats – for example the potential off-target effects of say inhibiting the activity of complement components. Also the strengths and weaknesses of the evidence in favour of this potential approach.

Guidelines for Scholarly Article

  • 1500 words.
  • Formal scientific language.
  • Addresses a scientific question that is directly related to the journal club articles.
  • The question the essay is going to answer is “What are the pathways (focus on proteins (c1q and c3)) should be considered  for future medication for the  neurodegenerative disease (mostly Alzheimer)?”
  • Discusses some of the specific findings in the articles that we have covered in the journal club series.
  • Within this guideline, you may choose to focus on a particular theme – for example

synapse loss in Alzheimer’s disease or developmental synaptic pruning mechanisms. You should mainly refer to the journal articles in our list, but you may supplement this with relevant article/s that you have found in your own research. Having said this, don’t feel that you must extensively research other articles – there are sufficient articles on our list to discuss.

  • You should discuss the roles of the complement proteins and their receptors. You should discuss the interplay between neurons and glia – microglia and astrocytes. You should highlight some specific evidence – molecular, cellular, electrophysiological, animal behaviour experiments etc; genetic and neuropathological evidence in humans.
  • You should discuss the strengths and weaknesses of the animal models and experimental evidence that has been used to evaluate these questions in the articles that we have covered.

Report Structure A. Title of proposal

The title should be brief but specific, providing a clear indication of what your review is about.

  1. Summary (<100 words: included in word count): Briefly explain what the question is and why it is important.
  2. Background and scientific Rationale (approximately 300-400 words): This section should focus on explaining the knowledge gap and the published scientific

evidence that led to the question being asked.

  1. Experimental evidence: Directly addressing the question (approximately 1000 words):

Divide into subheadings relevant to your review

Explain concisely the nature of the experiment. Briefly explain the:

– Animal model: genotype/s, age? Sex? and why it was chosen.

– Treatment for the experimental group: what experiment was done? at what age? for how long? Why this treatment regime?

– Control treatment: how does it differ and why is it necessary?

– Wild-type group? Genotype?. If so why necessary?

– Primary outcome measure: what was measured? What was the result?

– Sample size: do you think it was adequate?

-Strengths of the evidence relating to the scientific question; Weaknesses in the evidence.

  1. Overall conclusion and future outlook (50-100 words): briefly explain where things are at and where future research should be directed
  2. References cited (not included in word limit) Citations and the reference list should be in the Harvard format.

Do not cite papers you have not read.

General BACKGROUND info:

These 13 articles below focus on the Complement-cascade mediated synaptic homeostasis, chronic neurodegenerative and psychiatric disease

Stephan et al., 2013: “The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown.”

This series of papers looks at how a relatively newly discovered cellular process involving complement proteins in synaptic stripping during development of the CNS could be aberrantly re-activated in chronic neurodegenerative disease. This pathway may help explain the synapse loss that underlies cognitive decline in diseases as diverse as Alzheimer’s and Schizophrenia.

Introductory review paper:

Perry VH, O’Connor V. C1q: the perfect complement for a synaptic feast? Nat Rev Neurosci. 2008 Nov;9(11):807-11.

Articles to be used:

1) Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA. The classical complement cascade mediates CNS synapse elimination. Cell (2007) Dec 14;131(6):1164-78.

2) Schafer DP1, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012 May 24;74(4):691-705. doi: 10.1016/j.neuron.2012.03.026.

3) Paolicelli RC1, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT. Synaptic pruning by microglia is necessary for normal brain development.Science. 2011 Sep 9;333(6048):1456-8. doi: 10.1126/science.1202529. Epub 2011 Jul 21.

4) Shi Q, Colodner KJ, Matousek SB, Merry K, Hong S, Kenison JE, Frost JL, Le KX, Li S, Dodart JC, Caldarone BJ, Stevens B, Lemere CA. Complement C3-Deficient Mice Fail to Display Age-Related Hippocampal Decline. J Neurosci (2015) Sep 23;35(38):13029-42

5) Norris GT, Smirnov I, Filiano AJ, Shadowen HM, Cody KR, Thompson JA, Harris TH, Gaultier A, Overall CC, Kipnis J.Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury. J Exp Med. 2018 Jul 2;215(7):1789-1801. doi: 10.1084/jem.20172244.

6) Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE; Schizophrenia Working Group of the Psychiatric Genomics Consortium., Daly MJ, Carroll MC, Stevens B, McCarroll SA. Schizophrenia risk from complex variation of complement component 4. Nature (2016) Feb 11;530(7589):177-83.

7) Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science (2016) May 6;352(6286):712-6.

8) Wu T, Dejanovic B, Gandham VD, Gogineni A, Edmonds R, Schauer S, Srinivasan K, Huntley MA, Wang Y, Wang TM, Hedehus M, Barck KH, Stark M, Ngu H, Foreman O, Meilandt WJ, Elstrott J, Chang MC, Hansen DV, Carano RAD, Sheng M, Hanson JE. Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy. Cell Rep. 2019 Aug 20;28(8):2111-2123.e6. doi: 10.1016/j.celrep.2019.07.060.

9) Chung WS, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, Holtzman DM, Barres BA. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. (2016) Sep 6;113(36):

10) Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, Shang Y, Oldham MC, Martens LH, Gao F, Coppola G, Sloan SA, Hsieh CL, Kim CC, Bigio EH, Weintraub S, Mesulam MM, Rademakers R, Mackenzie IR, Seeley WW, Karydas A, Miller BL, Borroni B, Ghidoni R, Farese RV Jr, Paz JT, Barres BA, Huang EJ. Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell (2016) May 5;165(4):921-35.

11) Takahashi H, Klein ZA, Bhagat SM, Kaufman AC, Kostylev MA, Ikezu T, Strittmatter SM; Alzheimer’s Disease Neuroimaging Initiative. Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network. Acta Neuropathol. 2017 May;133(5):785-807. doi: 10.1007/s00401-017-1668-z. Epub 2017 Jan 9.

12) Weinhard L, di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, Exiga M, Vadisiute A, Raggioli A, Schertel A, Schwab Y, Gross CT. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction.Nat Commun. 2018 Mar 26; 9(1):1228.

13) Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA, Coutellier L, Kim L, Tsai HH, Huang EJ, Rowitch DH, Berns DS, Tenner AJ, Shamloo M, Barres BA. A dramatic increase of C1q protein in the CNS during normal aging. J Neurosci. (2013) Aug 14;33(33):13460-74.

Extra paper:

1) Kakegawa W, Mitakidis N, Miura E, Abe M, Matsuda K, Takeo YH, Kohda K, Motohashi J, Takahashi A, Nagao S, Muramatsu S, Watanabe M, Sakimura K, Aricescu AR, Yuzaki M. Anterograde C1ql1 signaling is required in order to determine and maintain a single-winner climbing fiber in the mouse cerebellum. Neuron (2015) Jan 21;85(2):316-29.


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