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BBA - Molecular Basis of Disease (v.1772, #4)

Editorial Board (pp. i).

Cell cycle dysregulation and neurodegenerative diseases by Mark A. Smith; Thomas Arendt; Inez Vincent; Xiongwei Zhu (pp. 391-391).

Cell cycle molecules define a pathway required for neuron death in development and disease by Lloyd A. Greene; David X. Liu; Carol M. Troy; Subhas C. Biswas (pp. 392-401).

We review here evidence defining a molecular pathway that includes cell cycle-related molecules and that appears to play a required role in neuron death during normal development as well as in disease and trauma. The pathway starts with inappropriate activation of cyclin dependent kinase 4 (Cdk4) in neurons which leads to hyper-phosphorylation of the pRb family member p130. This in turn results in dissociation of p130 and its associated chromatin modifiers Suv39H1 and HDAC1 from the transcription factor E2F4. Dissociation of this complex results in de-repression of genes with E2F binding sites including those encoding the transcription factors B- and C-Myb. Once elevated in neurons, B- and C-Myb proteins bind to the promoter for the pro-apoptotic BH3-only protein Bim and promote its induction. Bim then interacts with the core cellular apoptotic machinery, leading to caspase activation and apoptotic death. This pathway is supported by a variety of observations and experimental findings that implicate it as a required element for neuron loss in development and in many nervous system traumas and disorders. The components of this pathway appear to represent potential therapeutic targets for prevention of disease-associated neuron death.

Keywords: Neuron death; Apoptosis; Cell cycle; Cdk4; Myb; Bim

The dysregulation of the cell cycle and the diagnosis of Alzheimer's disease by Zsuzsanna Nagy (pp. 402-408).

The ‘silent epidemic’ of Alzheimer's disease is becoming a considerable social and economical problem in the developed countries. Especially so, because we still cannot diagnose the disease early enough, and there is no disease-modifying treatment. At present the only available therapeutic option is the use of cholinesterase inhibitors, which have mainly symptomatic short-term benefit for around one third of the patients . The solution to the problem would be the evidence-based design of early therapies, which could reverse/halt the cellular mechanisms that precede the formation of the typical brain pathology. The development of new therapeutic strategies, however, is hindered by limited knowledge of the pathogenic mechanisms that lead to the development of the sporadic form of the disease. Additionally, by the time the disease can be diagnosed, using the currently available diagnostic protocols, the pathology has spread to large areas of the brain, causing irreversible damage and functional disability . It is imperative therefore that we find early biomarkers for sporadic Alzheimer's disease, which could identify patients before substantial pathology develops.

Keywords: Alzheimer's disease; Cell cycle; Cyclin dependent kinase; cyclin dependent kinase inhibitor

The nature of the cell cycle in neurons: Focus on a “non-canonical” pathway of DNA replication causally related to death by Agata Copani; Filippo Caraci; Jeroen J.M. Hoozemans; Marco Calafiore; Maria Angela Sortino; Ferdinando Nicoletti (pp. 409-412).

The mechanism whereby a reactivation of cell cycle in neurons causes cell death is beginning to be identified. In cellular models of Alzheimer's disease, activation of a non-canonical pathway of DNA replication contributes to neuronal death. This pathway involves the repair enzyme DNA polymerase-β, which is highly expressed in neurons of the Alzheimer's brain at early stages of the disease. Loading of DNA polymerase-β into the replication forks generates a death signal, which involves the tumor suppressor p53. The increasing knowledge of the main actors of the unscheduled DNA replication in neurons will pave the way for novel therapeutic interventions in Alzheimer's disease and other neurodegenerative disorders.

Keywords: Alzheimer's disease; β-amyloid; DNA polymerase-β; APE-1; Cell cycle; DNA Replication; Apoptosis

Linking cell-cycle dysfunction in Alzheimer's disease to a failure of synaptic plasticity by Thomas Arendt; Martina K. Brückner (pp. 413-421).

Higher cerebral functions are based upon a dynamic organization of neuronal networks. To form synaptic connections and to continuously re-shape them in a process of ongoing structural adaptation, neurons must permanently withdraw from the cell cycle. In other words, synaptic plasticity can only occur on the expense of the ability to proliferate. Previously, we have put forward a hypothesis, coined “Dr. Jekyll and Mr. Hyde concept” that differentiated neurons after having withdrawn from the cell cycle are able to use those molecular mechanisms primarily developed to control proliferation alternatively to control synaptic plasticity [T. Arendt, Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways The Dr. Jekyll and Mr. Hyde Theory of Alzheimer's disease or The yin and yang of Neuroplasticity. Progr. Neurobiol. 71 (2003) 83–248]. The existence of these alternative effector pathways within a neuron might put it on the risk to erroneously convert signals derived from plastic synaptic changes into cell cycle activation which subsequently leads to cell death. Here we add further evidence to this hypothesis demonstrating a tight association of the origin recognition complex (ORC) with neurofibrillar pathology in AD. The ORC is a critical “guard” of DNA replication and point of convergence of numerous functionally redundant signaling pathways involved in cell cycle progression and transcriptional silencing of apoptotic programmes. ORC subunits in the mammalian brain and their homologes in Drosophila, however, have further been implicated in the regulation of structural neuronal plasticity and cognitive function. We propose that the abnormal subcellular distribution and segregation of ORC proteins in AD might compromise their physiological function in gene silencing and plasticity. This might result in cell cycle activation, DNA-replication and de-repression of apoptotic programmes. ORC subunits might, thus, provide a direct molecular link between synaptic plasticity, DNA replication and cell death.

Keywords: Alzheimer's disease; Cell cycle; Cell death; Origin recognition complex; Plasticity; Synapse

Pin1 in Alzheimer's disease: Multiple substrates, one regulatory mechanism? by Martin Balastik; Jormay Lim; Lucia Pastorino; Kun Ping Lu (pp. 422-429).

Presence of neuritic plaques and neurofibrillary tangles in the brain are two neuropathological hallmarks of Alzheimer's disease (AD), although the molecular basis of their coexistence remains elusive. The neurofibrillary tangles are composed of microtubule binding protein Tau, whereas neuritic plaques consist of amyloid-β peptides derived from amyloid precursor protein (APP). Recently, the peptidyl-prolyl cis/trans isomerase Pin1 has been identified to regulate the function of certain proteins after phosphorylation and to play an important role in cell cycle regulation and cancer development. New data indicate that Pin1 also regulates the function and processing of Tau and APP, respectively, and is important for protecting against age-dependent neurodegeneration. Furthermore, Pin1 is the only gene known so far that, when deleted in mice, can cause both Tau and Aβ-related pathologies in an age-dependent manner, resembling many aspects of human Alzheimer's disease. Moreover, in the human AD brain Pin1 is downregulated or inhibited by oxidative modifications and/or genetic changes. These results suggest that Pin1 deregulation may provide a link between formation of tangles and plaques in AD.

Keywords: Pin1; Isomerase; APP; Tau; Phosphorylation; Alzheimer's disease; Neurodegeneration

Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis by Rachael L. Neve; Donna L. McPhie (pp. 430-437).

The classic neuropathological diagnostic markers for AD are amyloid plaques and neurofibrillary tangles, but their role in the etiology and progression of the disease remains incompletely defined. Research over the last decade has revealed that cell cycle abnormalities also represent a major neuropathological feature of AD. These abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles; and it has been suggested that neuronal cell cycle regulatory failure may be a significant component of the pathogenesis of AD. The amyloid precursor protein (APP) is most commonly known as the source of the β-amyloid (Aβ) peptides that accumulate in the brains of patients with AD. However, a large body of work supports the idea that APP is also a signaling receptor. Most recently, it has been shown that familial AD (FAD) mutations in APP or simple overexpression of wild type APP cause dysfunction of APP signaling, resulting in initiation of DNA synthesis in neurons and consequent apoptosis. In this article, we review the evidence that APP has the potential to activate aberrant neuronal cell cycle re-entry in AD, and we describe a signal transduction pathway that may mediate this abnormal activation of the cell cycle.

Keywords: Alzheimer's disease; Amyloid precursor protein; p21 activated kinase; APP–BP1; Cell cycle; Apoptosis

Focal adhesions regulate Aβ signaling and cell death in Alzheimer's disease by John Caltagarone; Zheng Jing; Robert Bowser (pp. 438-445).

Alzheimer's disease (AD) is a neurodegenerative disorder that results from a loss of synaptic transmission and ultimately cell death. The presenting pathology of AD includes neuritic plaques composed of beta-amyloid peptide (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau, with neuronal loss in specific brain regions. However, the mechanisms that induce neuronal cell loss remain elusive. Focal adhesion (FA) proteins assemble into intracellular complexes involved in integrin-mediated communication between the extracellular matrix and the actin cytoskeleton, regulating many cell physiological processes including the cell cycle. Interestingly, recent studies report that integrins bind to Aβ fibrils, mediating Aβ signal transmission from extracellular sites of Aβ deposits into the cell and ultimately to the nucleus. In this review, we will discuss the Aβ induced integrin/FA signaling pathways that mediate cell cycle activation and cell death.

Keywords: Integrin; FAK; Paxillin; Cyclin D1; Alzheimer's disease; Cell cycle

Connecting cell-cycle activation to neurodegeneration in Drosophila by Vikram Khurana; Mel B. Feany (pp. 446-456).

Studies in cell-culture systems and in postmortem tissue from human disease have suggested a connection between cell-cycle activation and neurodegeneration. The fruit fly Drosophila melanogaster has recently emerged as a powerful model system in which to model neurodegenerative diseases. Here we review work in the fly that has begun to address some of the important questions regarding the relationship between cell-cycle activation and neurodegeneration in vivo, including recent data implicating cell-cycle activation as a downstream effector of tau-induced neurodegeneration. We suggest how powerful research tools in Drosophila might be utilized to approach fundamental questions that remain.

Keywords: Tau; Cell cycle; Neurodegeneration; Alzheimer's disease; TOR; Target of rapamycin; Mitogenic signaling; Apoptosis; Drosophila melanogaster; Invertebrate model

Cell division in the CNS: Protective response or lethal event in post-mitotic neurons? by Yan Yang; Karl Herrup (pp. 457-466).

Cell cycle events have been documented to be associated with several human neurodegenerative diseases. This review focuses on two diseases – Alzheimer's disease and ataxia telangiectasia – as well as their mouse models. Cell cycle studies have shown that ectopic expression of cell cycle markers is spatially and regional correlated well with neuronal cell death in both disease conditions. Further evidence of ectopic cell cycling is found in both human diseases and in its mouse models. These findings suggest that loss of cell cycle control represents a common pathological root of disease, which underlies the defects in the affected brain tissues in both human and mouse. Loss of cell cycle control is a unifying hypothesis for inducing neuronal death in CNS. In the disease models we have examined, cell cycle markers appear before the more well-recognized pathological changes and thus could serve as early stress markers—outcome measures for preclinical trials of potential disease therapies. As a marker these events could serve as a new criterion in human pathological diagnosis. The evidence to date is compatible with the requirement for a second “hit” for a neuron to progress cell cycle initiation and DNA replication to death. If this were true, any intervention of blocking ‘second’ processes might prevent or slow the neuronal cell death in the process of disease. What is not known is whether, in an adult neuron, the cell cycle event is part of the pathology or rather a desperate attempt of a neuron under stress to protect itself.

Keywords: Alzheimer; Ataxia Telangiectsia; Cell cycle; Neurodegeneration; APP mouse; atm-deficient; mouse

Neuronal cell cycle re-entry mediates Alzheimer disease-type changes by Andrew McShea; Hyoung-gon Lee; Robert B. Petersen; Gemma Casadesus; Inez Vincent; Nancy J. Linford; Jens-Oliver Funk; Robert A. Shapiro; Mark A. Smith (pp. 467-472).

Evidence showing the ectopic re-expression of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease led us to formulate the hypothesis that neurodegeneration, like cancer, is a disease of inappropriate cell cycle control. To test this notion, we used adenoviral-mediated expression of c- myc and ras oncogenes to drive postmitotic primary cortical neurons into the cell cycle. Cell cycle re-entry in neurons was associated with increased DNA content, as determined using BrdU and DAPI, and the re-expression of cyclin B1, a marker for the G₂/M phase of the cell cycle. Importantly, we also found that cell cycle re-entry in primary neurons leads to tau phosphorylation and conformational changes similar to that seen in Alzheimer disease. This study establishes that the cell cycle can be instigated in normally quiescent neuronal cells and results in a phenotype that shares features of degenerative neurons in Alzheimer disease. As such, our neuronal cell model may be extremely valuable for the development of novel therapeutic strategies.

Keywords: Alzheimer disease; Cell cycle; Phosphorylation; Tau

Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats by Yi Wen; Shao-Hua Yang; Ran Liu; Evelyn J. Perez; Anne Marie Brun-Zinkernagel; Peter Koulen; James W. Simpkins (pp. 473-483).

Although neurofibrillary tangle (NFT) formation is a central event in both familial and sporadic Alzheimer's disease (AD), neither cellular origin nor functional consequence of the NFTs are fully understood. This largely is due to the lack of available in vivo models for neurofibrillary degeneration (NFD). NFTs have only been identified in transgenic mice, bearing a transgene for a rare hereditary neurodegenerative disease, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP17). Epidemiological evidence suggests a much higher occurrence of dementia in stroke patients. This may represent the underlying cause of the pathogenesis of sporadic AD, which accounts for the majority of AD cases. We examined pathological markers of AD in a rodent stroke model. Here we show that after transient cerebral ischemia, hyperphosphorylated tau accumulates in neurons of the cerebral cortex in the ischemic area, forms filaments similar to those present in human neurodegenerative tauopathies and colocalizes with markers of apoptosis. As a potential underlying mechanism, we were able to determine that transient ischemia induced tau hyperphosphorylation and NFT-like conformations are associated with aberrant activation of cyclin dependent kinase 5 (Cdk5) and can be rescued by delivery of a potent, but non-specific cylclin dependent kinase inhibitor, roscovitine to the brain. Our study further indicates that accumulation of p35 and its calpain-mediated cleavage product, p25 may account for the deregulation of Cdk5 induced by transient ischemia. We conclude that Cdk5 may be the principal protein kinase responsible for tau hyperphosphorylation and may be a hallmark of the tauopathies in this stroke model.

Keywords: Tauopathy; Tau; Hyperphosphorylated tau; Neurofibrillary tangle; CDK5; Roscovitine

Cell cycle machinery and stroke by J. Rashidian; G.O. Iyirhiaro; D.S. Park (pp. 484-493).

Stroke results from a transient or permanent reduction in blood flow to the brain. The mechanisms involving neuronal death following ischemic insult are complex and not fully understood. One signal which may control ischemic neuronal death is the inappropriate activation of cell cycle regulators including cyclins, cyclin dependent kinases (CDKs) and endogenous cyclin dependent kinase inhibitors (CDKIs). In dividing cells, activation of cell cycle machinery induces cell proliferation. In the context of terminally differentiated-neurons, however, aberrant activation of these elements triggers neuronal death. Indeed, there are several lines of correlative and functional evidence supporting this “cell cycle/neuronal death hypothesis”. The objective of this review is to summarize the findings implicating cell cycle machinery in ischemic neuronal death from in vitro and in vivo studies. Importantly, determining and blocking the signaling pathway(s) by which these molecules act to mediate ischemic neuronal death, in conjunction with other targets may provide a viable therapeutic strategy for stroke damage.

Keywords: Stroke; CDKs; Cyclins; Cell cycle; Apoptosis

Alzheimer disease, the two-hit hypothesis: An update by Xiongwei Zhu; Hyoung-gon Lee; George Perry; Mark A. Smith (pp. 494-502).

Given the relative modality of single-insult models to accurately reflect Alzheimer disease pathogenesis, based on studies on mitogenic and oxidative stress signaling pathways, we proposed a two-hit hypothesis 2 years ago stating that both oxidative stress and mitogenic dysregulation are necessary and sufficient to cause the disease and suggested that it may be a common mechanism for other neurodegenerative diseases as well (X. Zhu, A.K. Raina, G. Perry, M.A. Smith, Alzheimer's disease: the two-hit hypothesis, Lancet Neurol. 3 (2004) 219–226.). Recent developments in the field confirm some important predictions of the hypothesis and shed new lights on potential mechanisms regarding how steady state may be achieved in sporadic AD cases and therefore, in our opinion, strengthen the hypothesis, which will be the focus of this review.

Keywords: Mitotic insult; Oxidative stress; AβPP; Tau; Mitotic steady state; Oxidative steady state

The cell cycle hypothesis of Alzheimer's disease: Suggestions for drug development by Jack Woods; Mike Snape; Mark A. Smith (pp. 503-508).

The cell cycle of hypothesis of neural dysfunction in chronic neurodegenerative conditions such as Alzheimer's disease (AD) offers a unified approach to understanding both existing and novel strategies for drug development. At the present time, a ligand based approach is a pragmatic solution for identifying new chemical leads on which to base future discovery and optimisation. We have pursued a ligand based approach on the basis of public domain data to identify existing compounds capable of abrogating the cell cycle at the G₀–G₁ interface. Selected on this basis, irrespective of the tissue under study, we identified several classes of compounds as potential chemical leads. Of these compounds, at least ten have already been shown to be neuroprotective in animal models of acute neurodegeneration. Such compounds could form the basis of a screening exercise after development of suitable screening tools. Progressing of chemical leads through such an approach will be more efficient if future leads display relevant “drug-like” properties. Further, drug development in this arena should take account of the special concerns raised by targeting an elderly population. This will involve accounting for frequent polypharmacy in the aging population, and age-related alterations in physiology.

Keywords: Alzheimer's disease; Cell cycle; Drug development; Neuroprotection

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BBA - Molecular Basis of Disease (v.1772, #4)