Summary

June Kinoshita, with Peter Davies, led this live discussion on 3 August 1999. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
  

Paper under discussion: Lu, Pei-Jung, Wulf, Gerburg, Zhou, Xiao Zhen, Davies, Peter, and Lu, Kun Ping. The propyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399, 784-788. 1999 Jun 24. Abstract

Transcript:

Live discussion held on Tuesday, 3 August 1999, 12-1 p.m. EST, and moderated by June Kinoshita

Participants: June Kinoshita, Peter Davies, Kun Ping Lu, Mark Smith, Dmitry Goldgaber, Ben Wolozin, Luc Buee.

Note: Transcript has been edited for clarity and accuracy.

June Kinoshita: Hello. Just checking this out.

Peter Davies: Hi June, just checking in.

MSmith: Everyone seems early. Am I in the wrong room?

Peter Davies: This is not the amyloid chat, if that's what you are looking for, Mark.

MSmith: A sick humor...I like that.

Luc Buee: Hi everybody.

June Kinoshita: Luc, why aren't you on vacation like everyone else in France?

Luc Buee: I am the youngest tenure position in the lab. I have to be at the bench.

June Kinoshita: Guest1, identify yourself!

guest1: Alex Osmand.

MSmith: Hi, Alex.

Luc Buee: Shall we start?

June Kinoshita: Where is Ping?

MSmith: Lets get ready to rumble....

Peter Davies: You sound in an aggressive mood today, Mark. Maybe we should send you to the amyloid chat.

June Kinoshita: Well, I think we can begin now. Welcome all! Pete Nelson wanted to join us today, but he couldn't make it. So I'll present the questions from his discussion. First, let's talk about tau's "normal" role in neuronal mitosis. Ping, would you like to respond?

Ccalz: I will try.

June Kinoshita: Take your time. Others are welcome to respond too, as long as we stick to this topic.

Peter Davies: Dmitry and I talked about this just a few hours ago. We don't know where tau is in mitosis, in any cell type

Ccalz: Neuronal mitosis likely occurs in fetal brains and stem cells in adult brain.

Luc Buee: Are we focusing on neuronal mitosis or is it possible to talk about cell mitosis?

June Kinoshita: We can broaden it to other cells. Where IS tau in mitosis?

MSmith: Also, specifically tau or tau phosphorylation?

Luc Buee: I think both aspects are important.

Ccalz: Tau is present in mitotic spindle in normal mitotic cells

Peter Davies: Can anyone cite a paper which shows immunofluorescence of tau in mitosis? (With a really specific antibody: most phosphoantibodies see other MAP's too.)

MSmith: I forget details, but Pope did a lot. Brion also, then there is vague recollection of a European Journal of Cell Science paper on this.

Peter Davies: I'm not convinced that tau has been visualized in mitotic cells at all.

Ccalz: Peter, do you means that your TG3 and other also recognize other MAPs?

Peter Davies: TG3 sees nucleolin as well as tau in mitotic cells. Dmitry showed this very convincingly

Ccalz: I think there are several papers looking at mitotic tau in tau overexpressing cells.

Luc Buee: Tau-1 also labels nucleole.

MSmith.: Do they have any alterations in proliferation? The tau overexpressors, that is.

Peter Davies: I have never seen a convincing double labeled mitotic cell I challenge anyone to show a picture of tau in a dividing cell.

June Kinoshita: We should have a picture contest!

Peter Davies: I agree with June.

MSmith: The challenge is there....let's post on site!

June Kinoshita: OK!

Ccalz: Mark, yes, I believe that they found that tau transient associates with MT.

June Kinoshita: Is the problem that tau antibodies are not specific enough?

Ccalz: How can we solve the problems about tau antibodies?

Peter Davies: There has been a real problem making stably transfected cells expressing decent amounts of tau. It seems they don't divide. We have plenty of good antibodies.

MSmith: Has anyone looked at expression of tau during mitosis?

Peter Davies: It is impossible to do without immunofluorescence

Luc Buee: Yes, during Xenopus oocyte maturation

MSmith: In synchronized cells????

Peter Davies: Where are the pictures, Mark?

MSmith: I am fast, but not that fast....I do not have on hand.

Peter Davies: Poor Dmitry must be going nuts.

dgoldgaber: I can see last entries. Dmitry.

Peter Davies: Welcome!

Ccalz: I remember I did see some papers looking tau-MT interaction in cultured cells.

Peter Davies: It is a critical question. Do tau and Pin1 see each other in a normal cell?

Ccalz: Peter, we have not looked at tau and Pin1 in mitotic cells yet, but will do so.

Peter Davies: I hope you are right, Ping

Ccalz: But I have to add that Pin1 is everywhere in mitotic cells, as expected from its binding a lot of mitotic proteins

June Kinoshita: What types of cells?

Ccalz: June, most of our studies are on HeLa cells and normal fibroblasts

June Kinoshita: Well, now that we've established the dimensions of our ignorance about tau and Pin1 in normal mitosis, let's expound on what these proteins are doing in mature neurons!

Peter Davies: We badly need to know where Pin1 is in normal neurons: our data, Ping, suggests it is nuclear.

Ccalz: My sense is that Pin1 is important for normal neurons to divide at fetal stage, but will be important for keeping postmitotic neurons from entering mitotic stage, which is lethal.

MSmith: What is Pin1 doing in diseased neurons?

Peter Davies: Yes, Mark, although it seems to be in tangles, but we don't know how early it gets there.

Ccalz: I agree with Peter.

June Kinoshita: Which goes awry first in AD: Pin1 or tau?

Peter Davies: I would love to think it's Pin1, but don't have the data

MSmith: Pin seems like some markers that we have been looking at related to the cell cycle, in that normally it's in nucleus but in AD it's in cytoplasm.

Luc Buee: Does Pin-1 always bind its substrates through one unique site?

Peter Davies: We need good icc antibodies for Pin1.

Ccalz: I feel that genetic alterations or other stimuli will somehow trigger neurons to enter cell cycle. This may be first.

MSmith: Maybe I missed it but is it just tangles or other neurons, and also, what about controls (aged)?

Ccalz: Luc, I think that Pin1 will bind and release.

Peter Davies: Only tangles in the cases we looked at, but there's lot's more to do.

Ccalz: Mark, Pin1 is in the nucleus in normal neurons.

June Kinoshita: To follow up on Ping's previous remark, what are the stimuli that are triggering neurons to enter the cell cycle?

Peter Davies: We need to do double labeling with Pin1 and the antibodies that Mark mentioned: cdc2, Cdk4, MC1 etc.

MSmith: June comes in with the easy questions!

Peter Davies: If anyone knows the answer to June's question, please share it.

June Kinoshita: I welcome speculations, the wilder the better!

MSmith: If only NFT, why would you think this is early? Come to think of it, why would you think this is bad?

Luc Buee: Elevated neuronal cdc2 like kinase activity in AD. An article just came out in Neuroscience Research

Peter Davies: What causes cells of the liver, or muscle, or lung, to re-enter the cell cycle? It is usually injury of some sort. But it can be genetic, or environmental, or smoking (Mark?)

dgoldgaber: A recent paper suggests that cyclin D is degraded by proteasome in neuronal cells undergoing differentiation. One can speculate that in AD proteasome is not functioning properly, cyclin D is not degraded, and neurons therefore may be pushed into the cell cycle by cyclin D and other proteins that are important in the initiation of mitosis.

MSmith: This may be stimulus?

MSmith: We are trying to address stimulus by following signaling pathways back to cell surface receptors...its painful

MSmith: Could AD be a cancer?

Peter Davies: If it looks like a duck, quacks like a duck

Ccalz: Ad is arrested cancer

MSmith: See cancer literature.

June Kinoshita: Wasn't this cancer idea proposed decades ago? Why hasn't it taken hold?

Ccalz: Cancer idea may be difficult to sell in most people's mind

Peter Davies: Too much attention on amyloid

MSmith: No!

Ccalz: As more cell cycle markers found in AD, cancer idea may come back.

Luc Buee: Is tau phosphorylation really a major issue in AD?

Peter Davies: To follow Luc's provocative line, the FTDP cases would argue that fooling with tau, as Pin1 seems to be doing, may not be good.

MSmith: Like fooling with amyloid?

Luc Buee: What is abnormal phosphorylation on tau? AT100 or PHF27-ir and phosphorylated Ser422. Is it related to cell cycle?

Ccalz: In normal cells, there are wide ranges of stimuli that can trigger cells to enter cell cycle.

MSmith: Does anyone think the increases in growth factors in AD brain may be responsible? Iqbal had a recent paper showing FGF causes increased tau phosphorylation.

Peter Davies: The Mandelkows show that phosphorylation of serine 214 dissociates tau from microtubules. This site is phosphorylated at only very low levels in the normal human or animal (J. Neurosci, in press).

Luc Buee: FGF binds HSPG, activates MAPK pathway and cell cycle... Why not??

MSmith: Luc, I like it. Activated MAPK is sky high in these neurons.

June Kinoshita: Can you update me on how growth factors are altered in AD?

MSmith: e.g., NGF increased...but, therapeutic trail still initiated I think.

Ccalz: There are many pathways leading to activation of MAP. How about stress?

Luc Buee: SAPK pathway (JNK, p38...)

MSmith: Ping, stress, oxidative stress, that was our interpretation in addition to cell cycle.

Ccalz: Mark, I think both stress and cell cycle can come together.

MSmith: What were results of NGF trial in AD?

Peter Davies: The NGF trial was a disaster in the first patients. No hard evidence of deficits, but it is complicated by the fact that activated glia produce lots of growth factors, and in AD....

MSmith: Perhaps it stimulated more cells into mitosis?

Ccalz: Mark, I agree.

Peter Davies: Whatever NGF did, was not good for the patients.

June Kinoshita: Very interesting. What happened to the patients?

Peter Davies: They were much worse, but only for the duration of treatment. It wore off.

Ccalz: Mark, do you know how stress works?

MSmith: Getting back to the paper, since Pin1 restores MT / tau-P....why MT alteration in AD?

Ccalz: Mark, at early stage, Pin1 can restore the function of tau, but not when it is depleted.

dgoldgaber: Prevention of amyloid depositions by immunization with amyloid peptide and activation of the immune system would also argue for "cancer-like" conditions in AD.

MSmith: That a trial I am NOT looking forward to.

Peter Davies: It may not be a good idea to try to suppress the immune response in AD.

June Kinoshita: Hi Ben! Glad you could make it.

Luc Buee: I do not understand how Ig can cross the BBB in these mice.

BWolozin: Hi June and Mark and Peter!

Peter Davies: Hi Ben.

June Kinoshita: Peter, why do you say it may not be a good idea to suppress immune response in AD?

Peter Davies: Because the immune system might be doing it's best to get rid of the junk accumulating in the AD brain, June

MSmith: But creating havoc in the process?

Ccalz: Does anybody think antibodies to tangles will have any benefit?

Peter Davies: The immune system may respond to more than just amyloid.

Luc Buee: The extracellular junk may be better than the intracellular. Thus inflammation process may not be so good.

dgoldgaber: The immune system probably works very well in people who will have AD (like those who have APP or PS1,2 mutations) but before they have the disease. But with age, like in cancer, it may fail to counteract the effects of the mutations and this may be the start of the disease.

Peter Davies: Dmitry and I think the same way.

MSmith: Did we get to the MT question?

Peter Davies: No: but again, we don't know whether changes in tau produced by Pin1 are good or bad: they may make tau more likely to form tangles.

Ccalz: Mark, Pin1 can restore tau function only at early stage, but would not have any effects, when it is depleted.

BWolozin: Can I ask some questions about pin1?

June Kinoshita: Yes!!

BWolozin: Since pin1 accumulates in tangles, wouldn't that reduce apoptosis?

MSmith smiles

MSmith: AHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHGH

BWolozin: Hmm, what does a smile mean?

Peter Davies: Is there apoptosis or mitosis in the AD brain?

Ccalz: Depletion of Pin1 into tangle may in fact induce apoptosis.

Luc Buee: Does Pin1 overexpression induce changes in tau expression?

Peter Davies: Luc: we don't know yet.

Ccalz: I do not know the effect of Pin1 overexpression on tau expression.

June Kinoshita: Mark, you're the apoptosis maven. What's your response to all of the above?

MSmith: Sounds like deja vu all over again......BTW, the noose broke!

BWolozin: OK, fine, forget apoptosis, but if there were mitosis, might you not see dividing stem cells (just to be provocative).

MSmith: You do.

BWolozin: Significantly?

MSmith: Neurons, not just stem cells , can in fact divide (Brewer showed this). He finds 70% in 3 year old rat neurons.

Peter Davies: Lots of stimulation of glial elements, remember.

BWolozin: True, lot's of glial stimulation.

dgoldgaber: Is it known to what molecules Pin1 binds in AD brains?

Peter Davies: Aside from tau, no.

Peter Davies: We don't know what Pin1 is doing in a non-dividing cell.

Ccalz: Pin1 likely binds other phosphoproteins in AD.

Peter Davies: I hope you are right, Ping

Luc Buee: Do we know if Pin1 binds to other phosphoproteins that are also glycosylated (O-GlcNac type)?

Ccalz: We do not know that

Ccalz: Peter, at least we are trying to identify other Pin1-binding proteins in AD.

Peter Davies: Sorry, I have to go. Thanks, everyone. It was fun!

BWolozin: Is there a pin1 knockout?

MSmith: So, Ping, what's next?

Ccalz: Yes there is Pin1 knockout

BWolozin: What is the phenotype in the brain?

Ccalz: We are examining the phenotype of Pin1 knockout in brain.

MSmith: Let's mate it with APP/PS1.

Luc Buee: OK, I am also leaving, Bye everybody, see you in Miami.

Ccalz: Mark, we are trying to determine whether Pin1 levels can alter NT phenotype.

June Kinoshita: The animals are viable?

MSmith: Pin overexpressor transgenic?

Ccalz: Mark, we are making Pin1 overexpressing transgenic.

MSmith: Would love to work on this when available.

Ccalz: Mark, I will let you know.

BWolozin: If pin1 turned on mitosis in neurons, wouldn't you see excess neuronal proliferation in the k/o?

Ccalz: Probably not.

BWolozin: Why?

Ccalz: There are other Pin1-like molecules.

BWolozin: Any idea how other pin1 like molecules respond in the AD brain?

Ccalz: We do not know yet.

June Kinoshita: We've run over the hour, so I would like to thank you all very much for attending.

Ccalz: Thank you, bye.

MSmith: I'll fix the noose for the next round of "Apoptosis and AD."

June Kinoshita: Stop in next week, Friday (13th) for our next live event!

dgoldgaber: Thank you everybody and good bye!

June Kinoshita: Thanks, Dmitry. Ciao!

MSmith : See yer.

June Kinoshita: Ben is a featured panelist next week. Beta catenin and beyond!!

BWolozin: Absolutely - to infinity and beyond. Ciao!

Background

Background Text
By Peter Nelson

Nature is under no obligation to be simple. The complexity of reality is underscored in the intriguing new paper by Pei-Jung Lu and colleagues regarding a role for mitosis-related Pin1 protein in tau protein biochemistry (ref. 7). The paper argues for an interaction that is important in both normal and Alzheimer's disease brain. Moreover, it involves a (relatively) novel paradigm of protein-protein interaction. This finding is of interest in many fields of biosciences, but in an applied way could be most germane to neurological conditions including Alzheimer's disease
The purpose of this mini-review is to provide some background into the different fields of biosciences that are pertinent to an understanding of the abovementioned paper; to discuss the paper itself; and to suggest some questions and ideas for discussion on this web page and the accompanying live chat.
When diverse scientific fields are brought together in a novel advancement, sparks fly, and scientists rush to the library to get background papers. The paper by Lu and colleagues involves the biochemistry of the cell cycle and related proteins; tau proteins, in normal and Alzheimer states; and Pin1 and the paradigm of phosphorylation-dependent prolyl isomerases. These separate "players" had given some hints of interacting (e.g., as described below), but never before in this direct manner.
The cell cycle refers to the process by which cells and their genes regulate replication, division, differentiation and apoptosis. There is a cyclic progression:

G0G1(first "gap")-->S(DNA synth)--->G2(second gap)--->M(mitosis)--->back to G1

This basic schema has been appreciated for years. In the past decade, however, an almost staggering amount of information has been added to describe how this cycle is regulated in healthy and diseased tissue. No doubt, more will come.

Cell Cycle Proteins in Alzheimer's Disease
The role of cell cycle proteins in Alzheimer's disease has been both suggestive and puzzling. For one thing, Alzheimer's disease presents clinically long after the cell cycle in neurons "should" be frozen (in G0). Yet cell cycle proteins have been detected via immunohistochemistry along with Alzheimer's pathology in neurons. For example, the following proteins have been detected up-regulated in Alzheimer's-affected neurons relative to controls: Ki-67 (an indicator of being out of the G0 state), Cyclin D (at G1/S interface), and Cyclin B1 (G2/M) (refs. 1,9,10). Other hints of mitotic activity involve the familial Alzheimer's-related gene, presenilin (ref. 6). If these neurons are not dividing, what are they doing? Presumably, there is a link between how cells divide and differentiate on the one hand, and how they cope with injury on the other. In Alzheimer's brain, there is apparently an up-regulation of pathways reminiscent of cycling cells. It remains to be seen if this response contributes to the health or further injury of a given nerve cell, and if it exacerbates the overall disease process.
Many of the cell cycle proteins are kinases, which attach phosphate moieties to proteins. In 1996, Lu and colleagues described a new paradigm for how protein "modules" (ref.6), including so-called WW domains, can be employed to attach one protein to another in a phosphorylation- dependent manner (downstream of kinase action). This paradigm had been foreshadowed by the manner in which SH2 domains facilitate binding when one protein contains a phosphorylated tyrosine residue. However, WW domains involve phosphorylated serines or threonines, and the WW domain interaction causes an "isomerase" bending of the affected protein molecule. Since the WW domains are a module that can attach to any protein, they are quite versatile.

Protein 1----------Phosphorylated Serine/Threonine

{protein-protein binding}

WW domain-mediated interaction----------------------Protein 2

{Change in Protein 2 function}

Pin1 (peptidyl-prolyl isomerase nucleoprotein) is an example of a versatile protein that contains a WW domain (key references include refs. 2,3,4,6,7,8,12,13,14,15). Most of the known substrates to which Pin1 binds through its WW domain are mitotic phosphoproteins. For example, Pin1 interacts with phosphorylated kinases (e.g., myt1, plk1), phosphatases (e.g. Cdc27), proteases (e.g. Nedd4), and the GTP binding protein Rab4. An important-seeming interaction involves Cdc25 and plx1, upstream regulators of Cdc2/cyclin B, in a manner that renders Pin1 an essential regulator of the cell cycle (too much Pin1 leads to cell cycle arrest in G2; depletion of Pin1 causes arrest of mitosis[ref.5]).

Summary of Paper Under Discussion
In the paper being presently discussed, Lu et al. provide data consistent with the hypothesis that that Pin1 and tau can interact with high specificity (ref.7). This begs the question: is tau protein a "mitotic phosphoprotein"? The prevailing hypotheses pertaining to tau protein focus on its role in tubulin binding and the subsequent seeding/bundling of microtubules. Through the effect on microtubules, tau is thought to play a role in the elaboration of neuronal processes (mainly the axon), developmental axon plasticity, and the maintenance of cell shape. However, some previous data support a connection between tau protein and cell cycle biochemistry. Tau protein has been shown to be:

  • minimally phosphorylated in neuronal cell lines in culture during interphase of cell division
  • highly phosphorylated in the same cell lines during mitosis (ref.11)
  • phosphorylated by cell cycle kinases
  • present in the nuclei of cells under certain circumstances
  • phosphorylated in neurofibrillary tangles of Alzheimer's disease in the same (as well as other) residues as during mitosis

These and other data imply a role for tau in cell cycle biochemistry (moreover, there is a lot of data to suggest that tau proteins may play other important roles in neuronal cell biology; remember, nature is under no obligation to be simple!). Pei-Jung Lu and colleagues have greatly extended the work connecting tau proteins and the cell cycle by the present study involving Pin1 and tau (ref. 7). Their findings include:

  • Tau proteins phosphorylated by mitotic Xenopus extracts (but not by interphase extracts) bind to GST-bound Pin1 in a pull-down assay
  • Likewise, AD tau but not normal tau binds GST-Pin1
  • Pin-1 binds to AD neurofibrillary tangles in situ.
  • Pin-1 is immunohistochemically found in normal neuronal nuclei
  • Pin-1 binds with high specificity to a single phosphorylated threonine residue on tau (pT231)
  • Tau that has been phosphorylated by Cdc2 binds to GST-Pin1 via a WW domain at pT231
  • Cdc2-phosphorylated tau has reduced microtubule-forming capabilities
  • Pin-1 binding of Cdc2-phosphorylated tau re-enables microtubule forming capabilities

Kinases are differentially depleted in Alzheimer brain neurons; whereas GSK-3-beta levels are relatively unchanged, and Cdc2 levels are increased, Pin-1 levels are decreased by approximately a factor of 5, leading the authors to posit that "sequestration of Pin-1 in PHFs depletes soluble Pin-1, which itself might also have a deleterious effect."

Some Discussion Topics
Whether all of the findings in this study will "stand up" to future critical analyses is unknown, obviously. What does seem robust is the interaction between Pin1 and phosphorylated tau at the pT231 residue. T231 resides in an evolutionarily well-conserved area of tau protein N-terminal to the microtubule-binding repeats (there are some mutations among mammalian species in residues between T231 residue and the binding repeats) (ref.11).
This study, as good studies do, raises novel questions. These include:

  • What is the pharmacology of the interaction between Pin1 and tau (can it be stimulated to improve the function of tau in Alzheimer's disease and other disorders with tangles?)?
  • Does this pathway have a direct role in cell death?
  • How important a role does tau have in neuronal mitoses?
  • Why is mitosis relevant at all in the context of mature neurons?
  • Does Pin1 directly "seed" PHFs?
  • What is the biochemistry of tau proteins in the nucleus, if any?

In addition to the direct relevance to Alzheimer's disease, the interaction of Pin1 and tau is titillating to researchers interested in tau molecule per se. Here is a novel mechanism that allows phosphorylated tau protein to be added on, almost like a Lego piece, to any module-containing protein. The implications are fantastic, almost limitless, to the applications that can now be performed by tau. It could help to explain the many diverse roles that have been suggested for tau (e.g. interactions with vesicles and ribosomes), as it may also help to explain why tau is so finicky an antigen in situ.
It may seem complicated and daunting to think of now, but, come to think of it, things tend to appear a bit simpler, in retrospect.

References
1. Busser J, Geldmacher DS, Herrup K. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. J.Neurosci. 1998 Apr 15;18:2801-2807. Abstract.

2. Campbell HD, Webb GC, Fountain S, Young IG. The human PIN1 peptidyl-prolyl cis/trans isomerase gene maps to human chromosome 19p13 and the closely related PIN1L gene to 1p31. Genomics 1997 Sep 1;44:157-162. Abstract.

3. Crenshaw DG, Yang J, Means AR, Kornbluth S. The mitotic peptidyl-prolyl isomerase, Pin1, interacts with Cdc25 and Plx1. EMBO J. 1998 Aug 10;17:1315-1327. Abstract.

4. Gothel SF, Marahiel MA. Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell Mol.Life Sci. 1999 Mar;55:423-436. Abstract.

5. Li,J.; Xu,M.; Zhou,H.; Ma,J.; Potter,H. Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation. Cell 1997: 90:917-927. Abstract.

6. Lu KP, Hanes SD, Hunter T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 1996 Apr 11;380:544-547. Abstract.

7. Lu, Pei-Jung, Wulf, Gerburg, Zhou, Xiao Zhen, Davies, Peter, and and Lu, Kun Ping. The propyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399, 784-788. 1999 Jun 24. Abstract.

8. Lu PJ, Zhou XZ, Shen M, Lu KP. Function of WW domains as phosphoserine- or phosphothreonine-binding modules. Science 1999 Feb 26;283:1325-1328. Abstract.

9. Nagy Z, Esiri MM, Cato AM, Smith AD. Cell cycle markers in the hippocampus in Alzheimer's disease. Acta Neuropathol.(Berl.) 1997 Jul;94:6-15. Abstract.

10. Nagy, Z, Esiri MM, Smith AD. Expression of cell division markers in the hippocampus in Alzheimer's disease and other neurodegenerative conditions. Acta Neuropathol. (Berl.) 1997 Mar; 93: 294-300. Abstract.

11. Nelson, P.T., Stefansson, K., Gulcher, J., Saper, C.B. Molecular evolution of Tau protein: implications for Alzheimer's disease. J. Neurochem. 1996 Oct; 67:1622-1632. Abstract.

12. Preuss U, Doring F, Illenberger S, Mandelkow EM. Cell cycle-dependent phosphorylation and microtubule binding of tau protein stably transfected into Chinese hamster ovary cells. Mol.Biol.Cell 1995 Oct;6:1397-1410. Abstract.

13. Ranganathan R, Lu KP, Hunter T, Noel JP. Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent. Cell 1997 Jun 13; 89:875-886. Abstract.

14. Shen M, Stukenberg PT, Kirschner MW, Lu KP. The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Genes Dev. 1998 Mar 1;12:706-720. Abstract.

15. Yaffe MB, Schutkowski M, Shen M, et al. Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science 1997 Dec 12;278:1957-1960. Abstract.

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References

Webinar Citations

  1. Pin1, Tau and the Cell Cycle in Alzheimer Disease

Paper Citations

  1. . The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature. 1999 Jun 24;399(6738):784-8. PubMed.

External Citations

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Further Reading

Papers

  1. . Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer's disease. J Clin Invest. 1999 Mar;103(6):R15-R21. PubMed.