Cell cycle markers in the hippocampus in Alzheimer's disease

Abstract

Using immunohistochemistry we have analysed the nuclear expression of cyclins A, B, D, and E in neurones in the hippocampi of control subjects and patients suffering from various neurodegenerative disorders including. Alzheimer's disease (AD). Cyclins A and D could not be detected but 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 results suggest that some neurones may have re-entered the cell cycle. 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 G0. The expression pattern of cyclin E indicates that re-entry into the cell cycle is possible even 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. Neurones with cyclin B-reactive nuclei in AD were AT8 positive but did not contain fully developed tangles. In neurones, where cyclin B is expressed, it would appear that the G1/S checkpoint has been bypassed and that the cell cycle is arrested in G2. It is proposed that these neurones do not have the opportunity for subsequent re-differentiation. Since factors known to be present in G2 seem to be responsible for microtubule destabilisation and hyperphosphorylation of tau we hypothesise that cell cycle disturbances may be important in the pathogenesis of AD.

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…The next step is the incorporation of a biotin tag to 3AT. Several biotin tags have been shown to be effective such as NHS-biotin (4), sulfo-NHS-SS-biotin (282,286,332), or biotin (199). The enrichment of the biotin-tagged peptides then occurs using an avidin (4) or a streptavidin (286) 1624 BUTTERFIELD ET AL.…”

Podocyte Mitosis – A Catastrophe

“…Replicative DNA synthesis in terminally differentiated neurons followed by failures of cell cycle completion is the main principle of cycle theory of Alzheimer’s disease (AD) [50, 51]. Vulnerable neurons of the AD brain exhibit biomarkers of cell cycle progression and DNA replication suggesting a re-entry into the cell cycle [52, 53]. A number of laboratories have reported the re-expression of various cell cycle proteins in neurons from patients with AD: cyclins A [52], B [52], D [53], and E [52], as well as CDKs [51], Proliferating Cell Nuclear Antigen (PCNA) [51, 52], Ki67 [52] and cyclin-dependent kinase inhibitors (CKIs) of both the Ink (Inhibitors of Kinases) and Cip/Kip (CDK interacting protein/Kinase inhibitory protein) families [54, 55].…”

“…Vulnerable neurons of the AD brain exhibit biomarkers of cell cycle progression and DNA replication suggesting a re-entry into the cell cycle [52, 53]. A number of laboratories have reported the re-expression of various cell cycle proteins in neurons from patients with AD: cyclins A [52], B [52], D [53], and E [52], as well as CDKs [51], Proliferating Cell Nuclear Antigen (PCNA) [51, 52], Ki67 [52] and cyclin-dependent kinase inhibitors (CKIs) of both the Ink (Inhibitors of Kinases) and Cip/Kip (CDK interacting protein/Kinase inhibitory protein) families [54, 55]. One study demonstrated increased levels of phosphorylated H3 (Ser 10), a key regulator in chromatin compaction during cell division, in neuronal cytoplasm in AD compared to controls, further supporting the hypothesis that neurons in AD are mitotically activated [56].…”

Increased p27, an essential component of cell cycle control, in Alzheimer's disease

“…Despite intensive effort, the pathogenesis of neuronal injury in AD is not completely understood. However, recent studies demonstrate that, in AD, a number of cell cycle elements are up-regulated in the susceptible neurones despite their terminally differentiated status (Masliah et al ., 1993;Smith & Lippa, 1995;Kondratick & Vandre, 1996;Li et al ., 1997;McShea et al ., 1997;Nagy et al ., 1997;Vincent et al ., 1997;Arendt et al ., 1998;Busser et al ., 1998;Illenberger et al ., 1998;Pei et al ., 1998;McShea et al ., 1999;Raina et al ., 2000;Zhu et al ., 2001;Ogawa et al ., 2003). Although the precise mechanism and significance of increased cell cycle elements in diseased neurones remains unclear, it has been suggested that cell cycle elements play a crucial role in neuronal death.…”