Inez Vincent led this live discussion on 7 August 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

See diagram from Inez Vincent

View Transcript of Live Discussion — Posted 29 August 2006

Background Text
By Inez Vincent

A fascinating mechanism for neurodegeneration in Alzheimer's disease has evolved in the last 5 years, namely that an inappropriate reactivation of the cell cycle is an early and important event in the development of AD. It defies all that we have believed about the terminal differentiation status of the neuron in mature brain. It implicates molecules that were thought to function exclusively as regulators of the cell division cycle and are not typically found in the largely non-proliferative brain.

This historic view was challenged recently on two fronts. First, studies of neurodegeneration in Alzheimer's and related disorders have indicated a resurgence of cell-cycle activity in degenerating, but not healthy, neurons. Second, techniques for detecting DNA synthesis in vivo and for unequivocal identification of newborn neuronal cells have demonstrated continued neurogenesis in normal adult brain. This newfound ability of adult brain to generate neurons from stem cells residing within the brain is being pursued intensely for its potential in replacing neurons lost to degeneration. However, we must realize that the neurogenic capacity of normal brain is quite distinct from the disease-associated reappearance of cell-cycle regulators, which takes place in neurons that have been postmitotic for decades since their origin in development.

Two major observations have helped establish the cell-cycle hypothesis for AD neurodegeneration. First, activation of cell-cycle regulators generally precedes formation of degenerative lesions, such as neurofibrillary tangles (NFTs), and the regulators and their downstream effectors eventually become incorporated into NFTs. Thus it has been postulated that cell-cycle regulators initiate and mediate the neurodegenerative process. Second, with the exception of karyo- and cytokinesis, markers from every phase of the cell cycle, and duplicated chromosomes, have been described in degenerating neurons. This has led to the hypothesis that vulnerable neurons re-enter the cell cycle and proceed through S phase, but then abort somatic division and eventually degenerate. I have been engrossed with this issue ever since our initial observations. Many questions preoccupy my mind:

• What triggers this 'final cycle,' and when?
• Are neurons truly postmitotic, or do they cycle very, very slowly?
• Is this unscheduled, inappropriate 'division' of postmitotic neurons akin to the dysregulated division of non-neuronal cells that culminates in neoplasia?
• Are neurodegeneration and neoplastic transformation - despite their opposite outcomes - driven by the same cellular mechanism?
• Are mutant AβPP, PS1 and PS2 neuro-oncogenes?
• Is neurodegenerative disease a 'cancer' of neurons?

A potential benefit of establishing such a connection is that it creates the opportunity for applying to the treatment of Alzheimer's disease a spectrum of candidate drugs being developed against cancer. Such a "joint venture" might provide a means for curbing two of the most costly health problems in our society.

If you are intrigued by this story, join us for our live online chat on May 20th, noon Eastern. To fuel our discussion, I have posited below some of the popular ideas pertaining to the cell-cycle hypothesis for AD neurodegeneration, along with data pro and con these ideas. Having chosen only a few sample references to support the arguments, I apologize to many who are not acknowledged. I am grateful to everyone who has contributed to establishing this new and exciting research area.

Postmitotic Neurons Degenerate Because of Inappropriate Cell Cycle Activation

YES

NO

Cell cycle markers increased in affected neurons in AD. (Rev by McShea, 99; Zhu, 99; Nagy 00; Arendt, 00; see Neurobiol. Aging ,21, 00) G0-G1: mitogenic/trophic factors and receptors, downstream signaling, increased pRb and E2F1 (Jordan-Sciutto, 02) G1-S: cdk4, cyclins E and A, PCNA, p105, Cdc25A, duplicated chromosomes. G2-M: cdc2, cyclin B1, Cdc25B, Wee1, cdk7, polo kinase, increased mitotic phosphorylation of nucleolin, RNA pol II, tau, Wee1, Cdc25A and B. Mitotically phosphorylated proteins are incorporated into NFT. Pin1 is sequestered in NFT and depleted in neurons, promoting mitosis (Lu, 1999). Increased mitochondria. AβPP and tau undergo cell cycle-dependent phosphorylation in dividing cells (Suzuki, 94; Preuss, 98; Zhang 00). Forced expression of oncogenes in neurons, (Feddersen, 95) and other postmitotic cells (Crescenzi, 95), leads to cell cycle re-entry followed by death.

Neuroscience dogma: terminally differentiated neurons incapable of division (Rakic, 85) Increased cdk inhibitors p15, p16, p21, in AD (Arendt 96; McShea, 97) inconsistent with cdk activation. Cdks and their regulators restricted to neuronal cytoplasm, while DNA synthesis and mitotic initiation occurs in nucleus (Husseman, 00) No evidence for karyo- or cytokinesisSimultaneous increases in G1 and M of Cdk activity is inconsistent with exquisite control of temporal fluctuations in normally dividing cells. Chromosomal reduplication may simply increase with aging (Goldberg, 84; Medvedev, 86; Borsatto 98; Fujisawa, 98; Wagner 01).Aneuploidy in neurons of mature mouse brain (Rehen, 01), has never been studied in human brain

What We Need: In vivo models to establish the role of cell-cycle regulators and progression of each cell-cycle phase in neurodegeneration.

Technical Caveat: Differentiated neuroblastoma and primary neuron cultures are quick and easy, but are not sustainable without cell-cycle aberrations. Neuroblastoma are transformed cells, often with gross chromosomal and checkpoint abnormalities. Primary neurons do not down-regulate cell cycle genes until 4-5 days in culture but most transfection experiments are initiated before this time. Primary neurons do not down-regulate cyclin B1 expression until about 10 days in culture! These systems are not truly postmitotic. They are OK for one-step relationships (e.g. does ectopic cdc2 expression generate mitotic phosphoepitopes,) but not for unraveling cell cycle mechanisms, signaling pathways, cellular phenomena.

In AD, Non-Neuronal Cells Also Have a Cell Cycle Defect

YES	NO
Failure of proliferation control in blood lymphocytes, low responsiveness to mitogenic compounds (Steiler, 01), higher sister chromatid exchange compared with young adults (Melaragno, 91), decreased responsiveness of lymphocytes to G1 inhibitors (Nagy, 02), increased proliferation of lymphoblasts (Urcelay, 01)	No changes in T lymphocyte subsets or proliferation (Leffell, 85), no change in mitogenic response of lymphocytes to phytohemagglutinin, pokeweed mitogen, concavalin A, and staph protein A (Araga, 90)

The Known Etiologic Factors AβPP, PS1/2 Are Consistent With the Hypothesis

YES

NO

Extracellular AβPP enhances proliferation of CNS-derived neural stem cells (Hayashi, 94; Ohsawa, 99), induces mitosis of Schwann cells (Alvarez, 95) is trophic for fibroblasts, epithelial (Pietrzik, 97) and epidermal basal cells (Hoffmann, 00), lymphocyte proliferation (Trieb, 96), PC12, neurons (Yamamoto, 94), Intracellular AβPP in colon carcinoma cells (Meng, 01). Overexpression of wild-type AβPP and FAD mutant AbPP-induced DNA synthesis in primary cortical neurons (Neve, 00) mediated by AβPP-BP1.Aβ induces cell cycle signaling and neuronal death (Copani, 99; Giovanni, 0l ;Wu, 00). PS-1 promotes neurogenesis in Xenopus (Paganelli, 01); PS1 deficiency increases cyclin D1 and entry into S phase, reversed by PS1 reexpression, but not by FAD mutants (Soriano, 01), PS-1 deficiency in cancer cells leads to tumor suppression, suggesting that PS-1 is required for tumor formation (Roperch, 98). 2 FAD mutations predispose to chromosome missegregation (nondisjunction) as evidenced by increased chromosome 21 trisomy mosaicism (Geller, 99), and an increase in association of a PS-1 intron 8 polymorphism in mothers of Down syndrome patients with meiosis errors (Petersen, 00); cdc2 binds and phosphorylates Aβ (Milton, 01). Cdk inhibitor blocks neuronal apoptosis in AbPPswe/ PS1-A246E mice (Xiang, 02)

No in vivo evidence exists that AbPP or FAD mutations causes cell cycle activation in neurons.Aβ inhibits endothelial cell replication in vitro (Grammas, 95). Overexpression of PS-1, PS-2, in HeLa cause G1 arrest in HEK2293 cells in S phase (Jeong, 00), and FAD mutants potentiate arrest (Janicki, 00) - does not affect levels of p21. No evidence for direct effects of PS-1 or 2 on cell cycle activation in mature brain.Brain PS-1 expression is downregulated in p53 deficient mice (Amson, 00).

What We Need: Examine cell cycle markers in the brains of mutant AβPP, PS, and AβPP/PS double transgenic mice; study effects of AβPP, PS, and ApoE4 on expression of specific cell cycle genes in differentiated primary neurons or neuroblastoma cells.

Cell Cycle Regulators Mediate Apoptosis, Not Cell Cycle Entry/Progression

YES

NO

(Rev Cotman, 00; Shimohama, 00; Yuan 00) DNA damage and fragmentation is increased in AD neurons, morphological apoptotic changes evident (Andersen, 01; Broe, 01). Cdk4 is an obligatory mediator of Bax- and caspase3-driven neuronal apoptosis, and could trigger apoptosis Caspases 1, 2, 3, 6, 8, 9, and 12 are implicated in Aβ-induced neuronal death in vitro, in animal models of neurodegen. diseases, and in AD brain (Roth, 01). Caspase cleavage products fodrin (Cotman, Rohn, 01), Bax, ZIP kinase, Bim/BOD, Bcl-2 and p21 (Yuan, 00; Engidawork, 01)are increased. 14-3-3 (Fountoulakis, 99), G1 cdks and cyclins are activated in in-vitro and in-vivo models for neuronal apoptosis, (Freeman, 94; Padmanabhan, 99; Liu, 01; Osuga, 00; Katchanov, 01; Chopp, 01)

(rev Raina 01; Roth 01) Frequency of DNA fragmentation in neurons too high to account for continuous, slow, neuronal loss over protracted disease period (Perry, 98) Increased cell cycle activity and NFT in neurons with intact nuclear membrane, no chromosomal condensation, no blebbing (Bancher 97; Husseman, 00; Raina 01) MAP kinase-phosphorylated c-Myc does not colocalize with caspase-3 activation in AD (Ferrer, 2001).

What We Need: Double labeling of AD brain sections with cell cycle and apoptotic markers to determine temporal and spatial overlap, analyses of cell cycle markers in transgenic mouse models displaying apoptosis

Activation of Cell Cycle Regulators Is a Regenerative Response

YES

NO

Increased Neuritic sprouting in AD. Extracts from AD brain stimulate branching of neurites in PC12 cells (Kittur, 92). Increased embryonic a-tubulin mRNA in AD (Miller 90).Increased 'fetal' tau phosphoepitopes in AD (Hasegawa, 93; Bramblett, 93; Goedert, 93). Increased levels of growth-associated proteins GAP-43 (Martzen 93; de la Monte, 95), spectrin, (Masliah, 91), MARK (Drewes, 98) in AD. Brain injury can promote neurogenesis:Increased cyclin D, cdk4, neurogenesis in response to ischemia (Chopp, 01, Osuga, 00; Jiang, 01; Kernie, 01), andincreased NSE and NF-positive mitotic figures after partial cortical ablation in adult rat (Huang, 90)

No evidence supporting a role for cell cycle regulators in regenerative neuritic sprouting in AD or any model. No evidence for activation of cell cycle mechanisms in postmitotic neurons following injury

What We Need: Double labeling for cell cycle markers and sprouting markers to illustrate presence in same neurons.

Cell Cycle Regulators Have Diversified Roles in Neurons

YES	NO
Cdc25A and B, and Wee1 are constitutively active in normal postmitotic neurons of brain (Ding 00; Tomashevski 01; Vincent 01). Cyclins A and B1 are commonly expressed in postmitotic neurons of middle aged and elderly humans (Pae and Vincent, unpublished), as are cyclin H (Jin, 99), andanaphase-promoting complex (Gieffers, 99).	Expression of cell cycle genes is generally not detected by whole brain Northern blot or PCR analysis. (However, the brain is not a homogeneous organ. If expression is localized to specific neuronal populations or brain regions, it may be missed by these methods)

What We Need: Systematic demonstration of such molecules by immunohistochemistry, western blot, in situ hybridization, PCR, in different regions of autopsy and biopsy brain from human/other primates; direct demonstration of the functions of these proteins in postmitotic neurons in vitro and in vivo.

Comment by Thomas Arendt
How do Cycling Neurons and AD Fit into the Big Scheme of Things?—Posted 14 May 2002

We understand a thing if we understand how it develops. This applies to both Alzheimer´s disease and the human brain.

Alzheimer´s disease is a chronic disorder with progressive neurodegeneration associated with a typical pathology: amyloid deposits and neurofibrillary tangle formation. While amyloid pathology is more uniformly distributed throughout the brain, tangle formation in different brain areas follows a particular sequence and always affects some areas earlier than others. Understanding this selective neuronal vulnerability to tangle formation is the key issue to understand Alzheimer´s disease.

Those brain areas and neuronal types that are highly vulnerable to tangle formation also differ from the rest of the brain in several other regards that might give us hints: They exhibit a particularly high degree of synaptic plasticity (and probably synaptic turnover), they have been acquired late during phylogenetic development (or have been completely re-organized during recent phylogenetic development), and they mature rather late during ontogenetic development.

Neurons are different from most other cells in the body in that they are highly polar and, thus, are probably the most differentiated cells in the true sense of the word. After proliferation, migration, and differentiation, they become integrated for a lifetime in a neuronal network. This integration requires intercellular communication that is largely regulated through synaptic plasticity. The neuron runs into problems, as cell connectivity and attachment are mechanisms that, during evolution from single-to multicellular systems, were acquired to control proliferation, differentiation, and cell death. For the differentiated, non-proliferative neuron, however, these mechanisms have become part of its genuine, plastic function. It is a common principle of evolution to re-use, at a certain phylogenetic point, a regulatory mechanism for a new biological function. For the neuron, controlling its synaptic plasticity is a great achievement, yet to do so at the expense of differentiation control may also put it at a permanent risk. Those neurons acquired late during brain evolution, for example cortical associative circuits that subserve typically human, higher cortical functions including learning, memory, reasoning, consciousness etc, need a particularly high degree of synaptic plasticity. This makes them supremely sensitive to lose differentiation control (and die?). While this appears like an evolutionary dead end, there is no selective pressure on this dead end as diseases associated with it, such as Alzheimer´s, occur after the reproductive period has ended.

Understanding Alzheimer´s disease and neurodegeneration within the framework of cellular differentiation and cell division control is an old idea. It first came up early in the 20th century (Cajal, 1928; Bouman´s theory of 'hyperdifferentiation,' 1934) and was repeatedly emphasized afterwards. Neurotrophic agents were suspected of exacerbating the pathologic cascade of Alzheimer´s disease, including its "aberrant neuronal growth". (Butcher and Woolf, 1989; Arendt, 1993; Heintz, 1993). It then became increasingly clear that mitogenic pathways in neurons are activated during early Alzheimer´s disease (Saitoh et al., 1993; Gärtner et al., 1995). More recently, insight into cell cycle control has seen major advances, been awarded a Nobel Prize, and the cell cycle itself came into direct focus of Alzheimer Research.

And still, we do not know how cellular differentiation is controlled in a neuron. Clearly, Alzheimer research might gain much if it learned from cancer biology and especially from developmental neurobiology.

I suggest these critical issues need to be tackled:

• How is neuronal differentiation regulated, and how is the differentiated stage fixed for a lifetime?
• What is the relationship between synaptic plasticity and neuronal differentiation? How do neuronal attachment, (synaptic) connectivity, and mitogenic stimulation come into these processes?
• Mechanisms known to mediate mitogenic effects during development: What are they doing in the adult brain (e.g. activation of the p21ras/MAPK pathway)?
• Is it possible to stabilize a neuron in its differentiated stage? Is this neuroprotective? Is this bad for synaptic plasticity and, thus, a restriction for higher brain function? Thomas Arendt, University of Leipzig, Germany.

References:
Ramon y Cajal S., 1928. Degeneration and regeneration of the nervous system. Oxford University Press, London.

Bouman L., 1934. Senile plaques. Brain 57, 128-142.

Arendt T, 1993. Neuronal dedifferentiation and degeneration in Alzheimer's disease. Biol. Chem. Hoppe-Seyler 374, 911-912.

	Comments on Live Discussion
	Comment by:  Inez Vincent, ARF Advisor
	Submitted 15 May 2002  |  Permalink	Posted 15 May 2002
	Reply from Inez Vincent Definitely, this would be worthwhile. Recent data supports the idea that phosphorylation of APP at the thr668 site alters its interaction with Fe65, and beta-amyloid production (Ando K,01). What needs to be determined is which kinase(s) phosphorylate(s) this site in vivo, especially in AD. Present evidence has implicated cdk5 (Iijima K, 00), cdc2 (Suzuki T, 94; Milton, 01 & 02), GSK-3β (Aplin AE, 96), stress-activated protein kinase 1b (Jun N-terminal kinase-3) (Standen CL, 01) and a novel kinase (Isohara T, 99). One way to approach this problem is to inhibit specific kinases in amyloid producing transgenic mice and determine whether this has any effect on amyloid production, and another would be to examine APP processing in many of the transgenic mouse models over expressing one of the proline-directed kinases, or mice deficient in activity of one of them. View all comments by Inez Vincent
	Comment by:  Tennore Ramesh
	Submitted 29 May 2002  |  Permalink	Posted 29 May 2002
	I wanted to join this the very interesting discussion but was unable to do so. As researcher at ALS-Therapy Development Foundation, I am involved in discovering new drugs to treat ALS. I propose a model that may explain the transition of neurons into the cell cycle and their eventual death. It goes like this: 1. Proteasomal dysfunction affects degradation of various cell-cycle regulators. 2. We believe polyamines are among the main players in this cell-cycle dysregulation. 3. Ornithine decarboxylase (ODC), the enzyme that converts ornithine to the polyamine precursor putrescine, is regulated at the post-translational level by the proteasome. 4. The polyamine-inducible protein antizyme and ODC interact, and proteasomal inhibition alters the proteasomal breakdown of ODC by antizyme. 5. This can lead to ODC accumulation and high polyamine levels in cells. 6. High polyamine levels can signal cells to enter the cell cycle by chromatin and histone destabilization and other mechanisms. 7. The conflicting proliferation and inhibitory signal can drive cells into...  Read more I wanted to join this the very interesting discussion but was unable to do so. As researcher at ALS-Therapy Development Foundation, I am involved in discovering new drugs to treat ALS. I propose a model that may explain the transition of neurons into the cell cycle and their eventual death. It goes like this: 1. Proteasomal dysfunction affects degradation of various cell-cycle regulators. 2. We believe polyamines are among the main players in this cell-cycle dysregulation. 3. Ornithine decarboxylase (ODC), the enzyme that converts ornithine to the polyamine precursor putrescine, is regulated at the post-translational level by the proteasome. 4. The polyamine-inducible protein antizyme and ODC interact, and proteasomal inhibition alters the proteasomal breakdown of ODC by antizyme. 5. This can lead to ODC accumulation and high polyamine levels in cells. 6. High polyamine levels can signal cells to enter the cell cycle by chromatin and histone destabilization and other mechanisms. 7. The conflicting proliferation and inhibitory signal can drive cells into apoptosis/death. - Tennore Ramesh, ALS Therapy Development Foundation, Newton, Massachusetts. References: 1. Toth & Coffino, 1999 Demonstrates that proteasome inhibition prevents ODC degradation 2. Chattopadhyay et al., 2001 Demonstrates that ODC is upregulated in neurons during aging and in neurodegenerative diseases such as Alzheimer's disease. 3. Virgili et al., 2001 4. Bernstein & Muller, 1999 5. Bernstein & Muller, 1995 Demonstrates that deregulation of ODC can affect neuronal differentiation. ODC inhibition is required for neuronal differentiation 6. Salzberg et al., 1996 View all comments by Tennore Ramesh
	Comment by:  Paul Coleman, ARF Advisor
	Submitted 29 May 2002  |  Permalink	Posted 29 May 2002
	Inez Vincent's background text is excellent. I would make one detailed comment about the part where she refers to Martzen et al., 1993, as showing an increase in GAP-43. In this paper we showed what we presumed to be a move of phospho GAP-43 between a cytosolic compartment and a membranous compartment. In fact, other papers from my lab have shown decreased expression of GAP-43 in AD homogenates of frontal association cortex (e.g. Coleman et al., 1992). Subsequently we showed that GAP-43 message was decreased in NFT neurons relative to adjacent NFT-free neurons ( Callahan et al., 1994), suggesting that the decrease we saw in homogenates was largely (not wholly - see next paragraph) due to those neurons with NFT rather than...  Read more Inez Vincent's background text is excellent. I would make one detailed comment about the part where she refers to Martzen et al., 1993, as showing an increase in GAP-43. In this paper we showed what we presumed to be a move of phospho GAP-43 between a cytosolic compartment and a membranous compartment. In fact, other papers from my lab have shown decreased expression of GAP-43 in AD homogenates of frontal association cortex (e.g. Coleman et al., 1992). Subsequently we showed that GAP-43 message was decreased in NFT neurons relative to adjacent NFT-free neurons ( Callahan et al., 1994), suggesting that the decrease we saw in homogenates was largely (not wholly - see next paragraph) due to those neurons with NFT rather than an equivalent decrease in all neurons. We cannot ignore the fact that papers exist in which immunohistochemical evidence indicated local GAP-43 immunoreactive sprouting. I believe these data and ours may be compatible if one assumes that although there may be some local sprouting, when looked at more globally in affected regions there is a net loss of GAP-43 expression. In one of our papers, we also showed no change in expression of GAP-43 in cerebellum in AD (Cheetham et al., 1996). A paper in press in Neuropath Exptl Neurol., using double immunohistochemistry (for NFT and for several phospho tau sites as well as in-situ hybridization for synaptophysin message, now shows convincingly that synaptophysin message decreases depending on phospho tau immunoreactivity. Phospho serine 396/404 does not seem to affect synaptophysin message expression in the cell body, but phospho serine 262 does (both the former occur in the absence of frank NFT). Formation of frank NFT results in a further reduction of synaptophysin message expression. Incidentally, these single neuron data were almost precisely the same regardless of whether the sections sampled came from Braak 5-6 or Braak 2-3 AD, suggesting that a tangle neuron is a tangle neuron and a phospho-tau neuron is a phospho-tau neuron without regard to disease state. In other words, within neuron types (e.g. pyramidal, stellate, etc., and regional location) cells with similar immunohistochemically-defined phenotypes are similar with respect to other variables, too, regardless of the disease stage of the brain. What makes the difference in overall disease status is the number of neurons in state X. View all comments by Paul Coleman
	Comment by:  Tennore Ramesh
	Submitted 31 May 2002  |  Permalink	Posted 31 May 2002
	Reply by Tennore Ramesh I agree with Dr. Wolozin. Many cell cycle proteins are regulated by the proteasome and that may be a simple starting point. CDk5 is shown to be altered in ALS. P35, the neuron-specific activator of CDK5, is regulated by the ubiquitin-proteasomal pathway and its half life is prolonged by proteasomal inhibition. Other pathways involved in cell cycle, such as the Jak-Stat pathway, are also regulated by the proteasome. Jak3 kinase inhibition significantly extended the life of SOD1 G93A mice, suggesting that modulation of these pathways may be a viable strategy in ALS and other neurodegenerative diseases. View all comments by Tennore Ramesh
	Comment by:  Nathaniel Milton (Disclosure)
	Submitted 15 May 2002  |  Permalink	Posted 29 August 2006
	The Cdc2 kinase phosphorylates amyloid-beta (Milton NGN. NeuroReport 12, 3839-3844, 2001) suggesting that cell cycle abnormalities may influence the plaque formation and neurodegeneration associated with elevated amyloid-beta. The amyloid-beta peptide also activates cdc2 directly and binds to cyclin B1(Milton NGN. Neurosci. Lett. 322, 131-133, 2002). Perhaps it is time to look at phosphorylated amyloid-beta as a causative agent rather than the normal unphosphorylated form. This form may also provide a more useful marker for neurodegenerative changes. View all comments by Nathaniel Milton
	Comment by:  Benjamin Wolozin, ARF Advisor (Disclosure)
	Submitted 29 May 2002  |  Permalink	Posted 29 August 2006
	Reply by Benjamin Wolozin I was pleased to see Dr. Ramesh's comment on the importance of the proteasome, and want to reiterate that proteasomal inhibition provides a simple explanation for the cell cycle connection to AD. Proteasomes regulate many cell cycle proteins, which certainly includes ODC, however I don't think that there is compelling evidence to suggest whether there is a particular cell cycle protein that triggers the entire process observed in AD. Thus, ODC is likely to be regulated by the proteasome, but whether it is the central protein in required for activating the cell cycle in AD brain remains unclear. View all comments by Benjamin Wolozin

	Submit a Comment on this Live Discussion
	Cast your vote and/or make a comment on this live discussion.  If you already are a member, please login. Not sure if you are a member? Search our member database. *First Name   *Last Name   Country or Territory: USA Canada Afghanistan Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burma Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos Islands Colombia Comoros Congo Cook Islands Corte d'lvoire (formerly Ivory Coast) Costa Rica Croatia Cuba Cyprus Czech Republic Denmark Djibouti Dominica Dominican Republic East Timor Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Gambia Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guinea Guinea-Bissau Guyana Haiti Heard and McDonald Islands Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Ivory Coast (now known as Corte d'lvoire) Jamaica Japan Jordan Kazakhstan Kenya Kiribati Korea, North Korea, South Kuwait Kyrgyzstan Laos Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macau Macedonia ( Former Yugoslav Republic of) Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Micronesia ( Federated States of) Moldova Monaco Mongolia Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island Northern Mariana Islands Norway Oman Pakistan Palau Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Island Poland Portugal Puerto Rico Qatar Reunion Romania Russia Rwanda S. Georgia and S. Sandwich Isls. Saint Kitts & Nevis Saint Lucia Saint Vincent and The Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Seychelles Sierra Leone Singapore Slovakia Slovenia Somalia South Africa Spain Sri Lanka St. Helena St. Pierre and Miquelon Sudan Suriname Svalbard and Jan Mayen Islands Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu U.S. Minor Outlying Islands U.S.A. Uganda Ukraine United Arab Emirates United Kingdom Uruguay Uzbekistan Vanuatu Vatican City Venezuela Vietnam Virgin Islands Wallis and Futuna Islands Western Sahara Yemen Yugoslavia (Former) Zaire Zambia Zimbabwe *Login Email Address   *Password    Minimum of 8 characters *Confirm Password   Stay signed in?   Comment: (If coauthors exist for this comment, please enter their names and email addresses at the end of the comment.) References: *Enter the verification code you see in the picture below: This helps Alzforum prevent automated registrations. Terms and Conditions of Use: Printable Version By clicking on the 'I accept' below, you are agreeing to the Terms and Conditions of Use above.