Alzheimer Disease: McShea A

Lee HG, Casadesus G, Zhu X, Castellani RJ, McShea A, Perry G, Petersen RB, Bajic V, Smith MA. · Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. · Neurochem Int. · Pubmed #19114068 No free full text.

Abstract: As one of the earliest pathologic changes, the aberrant re-expression of many cell cycle-related proteins and inappropriate cell cycle control in specific vulnerable neuronal populations in Alzheimer's disease (AD) is emerging as an important component in the pathogenesis leading to AD and other neurodegenerative diseases. These events are clearly representative of a true cell cycle, rather than epiphenomena of other processes since, in AD and other neurodegenerative diseases, there is a true mitotic alteration that leads to DNA replication. While the exact role of cell cycle re-entry is unclear, recent studies using cell culture and animal models strongly support the notion that the dysregulation of cell cycle in neurons leads to the development of AD-related pathology such as hyperphosphorylation of tau and amyloid-beta deposition and ultimately causes neuronal cell death. Importantly, cell cycle re-entry is also evident in mutant amyloid-beta precursor protein and tau transgenic mice and, as in human disease, occurs prior to the development of the pathological hallmarks, neurofibrillary tangles and amyloid-beta plaques. Therefore, the study of aberrant cell cycle regulation in model systems, both cellular and animal, may provide extremely important insights into the pathogenesis of AD and also serve as a means to test novel therapeutic approaches.

McShea A, Marlatt MW, Lee HG, Tarkowsky SM, Smit M, Smith MA. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · J Neuropathol Exp Neurol. · Pubmed #17086099 No free full text.

Abstract: Microarray technology is a tremendously powerful method for simultaneously monitoring the expression of thousands of species of nucleic acids, usually cellular mRNA, producing a high-resolution representation of the genes encoded or expressed in a cell. As such, microarray technology has great potential for impacting research and clinical approaches to treatment. However, this complex technology has been challenging to apply as a result of difficulties discerning biologic variation from technologic issues, therefore slowing the application of the technology to human diagnostics. Nevertheless, significant advances in microarray technology, improvements that avoid potential pitfalls, and a wider spectrum of application are making this technology easier to apply. Indeed, microarray technology has provided valuable insights into mechanisms involving gene regulation and expression in Alzheimer disease, and it remains a powerful tool to identify biomarkers for disease diagnosis. Ultimately, the most robust markers will enable the application of more specific treatments particular to disease stages or subcategories. Currently, no widely applicable molecular test is available to identify those at risk for developing Alzheimer disease or those who have early markers of pathology but show discernible cognitive impairment. The progression of this technology will lead to earlier detection of the disease through enhanced understanding of disease onset and progression.

Raina AK, Monteiro MJ, McShea A, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, Ohio, USA. · Int J Exp Pathol. · Pubmed #10469261 No free full text.

Abstract: The mechanism(s) underlying selective neuronal death in Alzheimer's disease remain unresolved. However, recently, we and others showed that susceptible hippocampal neurones in Alzheimer's disease express markers common to cells in various phases of the cell cycle. Since neuronal maturation is associated with effective escape from the cell division cycle, emergence out of quiescence may be deleterious. Here, we review a number of current findings indicating that disregulated ectopic re-activation of cell cycle-mediated events, akin to neoplasia, represent an important early pathway associated with neuronal death and, more importantly, one that involves virtually the entire spectrum of the pathological events described in Alzheimer's disease.

McShea A, Lee HG, Petersen RB, Casadesus G, Vincent I, Linford NJ, Funk JO, Shapiro RA, Smith MA. · Department of Biology, CombiMatrix Corp, Mukilteo, WA 98275, USA. · Biochim Biophys Acta. · Pubmed #17095196 No free full text.

Abstract: 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.

Zhu X, McShea A, Harris PL, Raina AK, Castellani RJ, Funk JO, Shah S, Atwood C, Bowen R, Bowser R, Morelli L, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. · J Neurosci Res. · Pubmed #14991845 No free full text.

Abstract: Adult neurons are generally accepted to be in a quiescent, nonproliferative state. However, it is becoming increasingly apparent that, in Alzheimer's disease (AD), alterations in cell cycle machinery, suggesting an attempt to reenter cell cycle, relate temporally and topographically to degenerating neurons. These findings, together with the fact that neurons lack the necessary components for completion of mitosis, have led to the notion that an ill-regulated attempt to reenter the cell cycle is associated with disease pathogenesis and, ultimately, neuronal degeneration. To understand better the role of such cell cycle abnormalities in AD, we undertook a study of CIP-1-associated regulator of cyclin B (CARB), a protein that associates with two key proteins, p21 and cyclin B, involved in cellular checkpoints in the cell cycle. Our results show that there are increases in CARB localized to intraneuronal neurofibrillary tangles and granulovacuolar degeneration in susceptible hippocampal and cortical neurons in AD. By marked contrast, CARB is found only at background levels in these neuronal populations in nondiseased age-matched controls. Our data not only provide another line of evidence indicative of cell cycle abnormalities in neurons in AD but also lend further credence to the hypothesis that susceptible neurons may be arrested at the G2/M phase of the cell cycle before they die. Therefore, therapeutics targeted toward initiators of the cell cycle are likely to prove of great efficacy for the treatment of AD.

Harris PL, Zhu X, Pamies C, Rottkamp CA, Ghanbari HA, McShea A, Feng Y, Ferris DK, Smith MA. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. · Neurobiol Aging. · Pubmed #11124427 No free full text.

Abstract: Neurons of adults apparently lack the components necessary to complete the cell division process. Therefore, in Alzheimer disease, the increased expression of cell cycle-related proteins in degenerating neurons likely leads to an interrupted mitotic process associated with cytoskeletal abnormalities and, ultimately, neuronal degeneration. In this study, to further delineate the role of mitotic processes in the pathogenesis of Alzheimer disease, we undertook a study of polo-like kinase (Plk), a protein that plays a crucial role in the cell cycle. Our results show disease-related increases in Plk in susceptible hippocampal and cortical neurons in comparison to young or age-matched controls. An increase in neuronal Plk further implicates aberrations in cell cycle control in the pathogenesis of Alzheimer disease and provides a novel mechanistic basis for therapeutic intervention.

Gerst JL, Raina AK, Pirim I, McShea A, Harris PL, Siedlak SL, Takeda A, Petersen RB, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. · J Neurosci Res. · Pubmed #10686596 No free full text.

Abstract: Alterations in cell-matrix 'contact' are often related to a disruption of cell cycle regulation and, as such, occur variously in neoplasia. Given the recent findings showing cell cycle alterations in Alzheimer disease, we undertook a study of ADAM-1 and 2 (A Disintegrin And Metalloprotease), developmentally-regulated, integrin-binding, membrane-bound metalloproteases. Our results show that whereas ADAM-1 and 2 are found in susceptible hippocampal neurons in Alzheimer disease, these proteins were not generally increased in similar neuronal populations in younger or age-matched controls except in association with age-related neurofibrillary alterations. This increase in both ADAM-1 and 2 in cases of Alzheimer disease was verified by immunoblot analysis (P < 0.05). An ADAM-induced loss of matrix integration would effectively "reset" the mitotic clock and thereby stimulate re-entry into the cell cycle in neurons in Alzheimer disease. Furthermore, given the importance of integrins in maintaining short-term memory, alterations in ADAM proteins or their proteolytic activity could also play a proximal role in the clinico-pathological manifestations of Alzheimer disease.

McShea A, Wahl AF, Smith MA. · Bristol-Myers Squibb, Pharmaceutical Research Institute, Seattle, Washington, USA. · Med Hypotheses. · Pubmed #10459833 No free full text.

Abstract: Several recent findings demonstrated increased expression of cell cycle-related proteins in the degenerating neurons found in Alzheimer disease. We hypothesize that this apparent attempt to re-enter the cell cycle is a neuronal response to external growth stimuli that leads to an abortive re-entry into the cell cycle. However, since neurons of adults apparently lack the capacity both to divide in vivo and in vitro, it is possible that they lack the components necessary to complete the cell division process. Nonetheless, the importance of these findings is that they provide an explanation for the increased phosphorylation of cytoskeletal proteins such as tau and neurofilaments that represent the most striking intracellular changes in the disease. Further, it is our contention that inappropriate reentry into the cell cycle and interrupted mitotic processes are significant factors not only in the cytoskeletal pathology but also in the neuronal degeneration that characterizes the pathology of Alzheimer disease.

McShea A, Zelasko DA, Gerst JL, Smith MA. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. · Brain Res. · Pubmed #9878757 No free full text.

Abstract: Hippocampal and select cortical neuronal populations in Alzheimer's disease exhibit phenotypic changes characteristic of cells re-entering the cell division cycle. Therefore, in this study, we investigated whether components, known to trigger cellular proliferation and differentiation, upstream of the ras/mitogen-activated kinase pathway, could contribute to the activation of a signal transduction cascade in Alzheimer's disease. We found that proteins implicated in signal transduction from cell surface receptors via the ras pathway, namely Grb2 and SOS-1, were altered in cases of Alzheimer's disease in comparison to age-matched controls. SOS is increased in susceptible pyramidal neurons, while Grb2 shows more subtle alterations in subcellular distribution. Importantly, both SOS-1 and Grb2 show considerable overlap with early cytoskeletal abnormalities suggesting that the alteration in signal transduction molecules is a concurrent, if not preceding, event in the pathogenesis of Alzheimer's disease. Taken together with the cell cycle abnormalities previously reported, these findings suggest that a signal derived from the cell surface contributes to a stimulus for neurons in Alzheimer's disease to re-enter the cell cycle.