НЕЙРОХИМИЯ, 2004, том 21, № 4, с. 245-249
ОБЗОРЫ
y^K 577.352
CELL CYCLE INDUCTION IN POSTMITOTIC, MATURE NEURONS AND NEURODEGENERATION: A BASIS FOR NOVEL THERAPEUTIC STRATEGIES IN NEURODEGENERATIVE DISEASES?
© 2004 N. V. Gulyaeva*
Department of Functional Biochemistry of the Nervous System, Institute of Higher Nervous Activity and Neurophysiology RAS, Moscow
Recent data suggest that induction of cell cycle in terminally differentiated, mature neurons precedes cell death in different neurodegenerative diseases. Factors involved in this aberrant cell cycle in postmitotic neurons may be most important targets for the design of pathogenetically directed treatment and prevention of neurodegen-erative diseases.
Key words: cell cycle, neurodegeneration, neurodegenerative diseases.
Neurons are distinctive in that they are generally considered to be permanently post-mitotic cells. Vertebrate neuron cell death may be both a normal developmental process and the catastrophic outcome of nervous system trauma or degenerative disorders. Though, in both cases the programmed death of neurons is defined as "apoptosis", obviously, both the triggers, and molecular details of these types of neuronal death are different.
Neurodegenerative diseases (ND) are devastating pathologies that are correlated with a region-specific neuronal cell loss. The number of Alzheimer's disease (AD) and other ND sufferers shows an alarming increase throughout the world. Therefore elucidation of the pathogenic mechanisms underlying neuronal death in ND, as well as the design of effective treatment, preventive or curative, is becoming imperative. Despite progress in uncovering many of the factors that contribute to the etiology of ND, the cause of the nerve cell death remains unknown. In our view, the most promising theory is that the neurons degenerate because they re-enter a lethal cell cycle (CC).
Almost a decade ago, Herrup and Busser [1] demonstrated that induction of multiple CC events preceded target-related neuronal death. Unexpected nerve cell death has been reported in several experimental situations where neurons have been forced to re-enter the CC after leaving the ventricular zone and entering the G0, non-mitotic stage. Herrup and Busser have examined target-related cell death in two neuronal populations, the granule cells of the cerebellar cortex and the neurons of the inferior olive. Mouse neurological mutant, staggerer (sg/sg), was characterized by intrinsic Purkinje cell deficiencies and, in this mutant, substantial numbers of cerebellar granule cells and inferior ol-
* Адресат для корреспонденции: 117485 Москва, ул. Бутлерова, д. 5А; e-mail:nata_gul@pisem.net
ive neurons die due to the absence of trophic support from their main postsynaptic target. The levels of three CC markers - cyclin D, proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) incorporation - were elevated in the granule cells before they die. While application of the TUNEL (in situ terminal transferase end labeling of fragmented DNA) technique failed to label dying granule cells in either mutant; light and electron microscopic observations were consistent with the interpretation that the death of these cells was apoptotic in nature. Together, these data indicated that target-related cell death in the developing central nervous system is associated with a mechanism of cell death that involves an apparent loss of CC control [1].
CC regulators have been shown to be involved in neuronal death evoked by excitotoxic stress [2]. Exci-totoxic stress is potentially an important component of disorders such as stroke and ND. Its toxic effects appear to be transduced through mechanisms that result in both acute and delayed forms of death. Nuclear localized cyclin D1, an activator of cyclin-dependent kinase (CDK)4/6, was upregulated during kainic acid evoked death of CA3/CA1 hippocampal neurons and this up-regulation was associated with increased phosphoryla-tion of a critical CDK substrate, retinoblastoma protein (pRb). In addition, CDK inhibitor, flavopiridol blocked the delayed death of cultured cortical neurons evoked by 3-nitroproprionic acid, an inhibitor of the mitochondrial electron transport chain; treatment and the NMDA antagonist, MK801 provided short-term protection in this model. Full and long-term protection occured when both flavopiridol and MK-801 were present. These data support a role for CC regulators in neuronal death evoked by excitotoxic stress.
Aggregates of P-amyloid peptide, the main constituent of amyloid plaques in Alzheimer's brain, kill neurons by a not yet defined mechanism, leading to apop-totic-like death. Herrup's group showed that p-amyloid
activated microglia induced CC and cell death in cultured cortical neurons [3]. Cultures of mouse cortical neurons were exposed to P-amyloid alone, microglial cells alone, or microglial cells activated by P-amyloid. Increased cell death was found in response to each of these treatments, however, only the amyloid activated microglial treatment increased the number of neurons that were positive for CC markers such as PCNA or cy-clin D and incorporation of BrdU. Double labeling with BrdU and TUNEL techniques verified that the "dividing" neurons were, in fact, dying, most likely through an apoptotic mechanism. Thus, P-amyloid activated microglia might play in leading neurons to re-express CC components. These results support a model in which microglial activation by P-amyloid is a key event in the progression in AD.
Simultaneously, another group has shown that mitotic signaling by P-amyloid causes neuronal death [4]. Both full-length p-amyloid peptide (1- 40) or (1-42) and its active fragment P-amyloid peptide (25-35) act as proliferative signals for differentiated cortical neurons, driving them into the CC. The cycle followed some of the steps observed in proliferating cells, including induction of cyclin D1, phosphorylation of pRb, and induction of cyclin E and A, but did not progress beyond S phase. Inactivation of CDK-4 or CDK-2 prevented both the entry into S phase and the development of apoptosis in P-amyloid peptide (25-35)-treated neurons. It has been concluded that neurons must cross the G1/S transition before succumbing to P-olecule that lies at the border between cell proliferation and apoptotic death, Copani et al. [5] focused on the disialoganglioside GD3. Exposure of rat cultured cortical neurons to 25 |M P-amyloid peptide (25-35) induced a substantial increase in the intracellular levels of GD3 after 4 hours, a time that precedes neuronal entry into S phase. GD3 synthesized in response to P-amyloid peptide (25-35) colocalized with nuclear chromatin. A causal relationship between GD3, CC activation, and apoptosis was demonstrated by treating the cultures with anti sense oligonucleotides directed against GD3 synthase. This treatment, which reduced P-amyloid peptide (25-35)-stimulated GD3 formation by about 50%, abolished the neuronal entry into the S phase.
From all ND, the postmortal brain of patients with AD is most thoroughly studied from the perspective of the aberrant CC. Using immunohistochemistry, Nagy et al. [6] have analyzed the nuclear expression of cy-clins A, B, D, and E in neurons in the hippocampi of control subjects and patients suffering from various ND including AD. Varying degrees of cyclin E expression were found in all patient groups including control subjects. Cyclin B expression was not detected in control subjects but it was expressed in the subiculum, dentate gyrus and CA1 region in patients with AD-type pathology and in the CA2 region and the dentate gyrus of cases of Pick's disease. These reults suggest that some neurons may have re-entered the CC. The expression of
cyclin E without cyclin A expression may indicate an arrest in G1 with the possibility of re-differentiation and exit from G1 to GO. The expression pattern of cyclin E indicates that re-entry into the CC is possible event in control patients, but it is accentuated in patients with AD-related pathology. However, cyclin B was only expressed in Ad patients and occurred in areas that were severely affected by pathology. Neurons with cyclin B-reactive nuclei in AD were AT8 positive but did not contain fully developed tangles. In neurons, where cyclin B is expressed, it would appear that the G1/S checkpoint has been bypassed and that the CC is arrested in G2. It is proposed that these neurons do not have the opportunity for subsequent re-differentiation. Since factors known to be present in G2 seem to be responsible for microtubule destabilization and hyper-phosphorylation of tau it has been suggested that CC disturbances may be important in the pathogenesis of AD [6].
Some other groups have described CC-related protein expression in vascular dementia and AD. Smitha et al. [7] studied the expression patterns of cyclins A, B1, D1 and E in neuronal nuclei in the hippocampus in au-topsied healthy elderly individuals, AD patients and subjects suffering from cerebro-vascular disease with and without co-existing AD. Nuclear cyclin B1 and cy-clin E expression was detected in hippocampal neurons in each subject category. However, cyclin B1 expression was elevated in the CA1 of patients suffering from cerebro-vascular disease alone, while cyclin E expression was higher in the CA4 subfield in patients suffering from mixed AD and cerebro-vascular diseases compared to subjects in other categories. The authors hypothesize that CC re-entry may occur in healthy elderly people leading to age-related cell death and mild Alzheimer-type pathology in the hippocampus. However, in pathological conditions, the Cc arrest may lead either to the development of severe Alzheimer-related pathology or to excess apoptotic cell death as in vascular dementia [7]. Ueberham et al. [8] presented the data confirming the involvement of cyclin C expression in the pathogenesis of AD.
Herrup's group made a major contributi
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