Andrew McShea

Signal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli

Hippocampal and select cortical neuronal populations in Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers disease to re-enter the cell cycle.

Cell cycle re-entry mediated neurodegeneration and its treatment role in the pathogenesis of Alzheimer's disease

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 Alzheimers 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.

The role of cell cycle‐mediated events in Alzheimer's disease

The mechanism(s) underlying selective neuronal death in Alzheimers disease remain unresolved. However, recently, we and others showed that susceptible hippocampal neurones in Alzheimers 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 Alzheimers disease.

Clinical benefit and preservation of flavonols in dark chocolate manufacturing.

The consumption of high-cacao-content chocolate has been associated with positive health benefits ascribed to flavanol [corrected] antioxidants derived from the ground, fermented cocoa seeds of Theobroma cacao. However, flavanols [corrected] impart a bitter, astringent flavor to foodstuffs, frequently masked in chocolates and confections by aggressive processing and adulteration with other flavors. Recent reports have implied that not all varieties of dark chocolate are created equally, and significant caveats exist regarding its potential health benefits. It is perhaps not surprising that extensive processing, dilution, and the addition of flavor modifiers may improve the palatability of chocolate, but could have negative nutritional and clinical benefits. This article examines the chemical composition of chocolate and the clinical data associated with the consumption of flavonoid-rich cocoa. We review the steps in chocolate manufacturing that directly affect the antioxidant levels in chocolate products, and the caveats associated with claims of health benefits from the consumption of dark chocolate.

Neuronal polo-like kinase in Alzheimer disease indicates cell cycle changes

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.

Neuroprotective effect of cocoa flavonids on in vitro oxidative stress

BackgroundCocoa is a rich source of flavonoids that, among other functions, can act as antioxidants. In living systems, the production of reactive oxygen species (ROS) activate an array of intracellular cascades, including mitogen-activated protein kinases (MAPK), that are closely associated with cell death or survival pathways.Aim of the studyTo ascertain the role of a cocoa extract and its main flavonoid, (-)-epicatechin, in an in vitro model of oxidative stress induced in a neuronal cell line.MethodsWe analyzed ROS production by fluorometry (dichlorofluorescein assay), and activation of MAPK pathways including extracellular signal-regulated kinases 1/2 (ERK 1/2), c-Jun N-terminal kinase (JNK), and p-38, by Western blot analysis.ResultsCells incubated with cocoa extract or (-)-epicatechin, reduced ROS production in a dose-dependent manner, reaching 35% inhibition. pJNK and p38, involved in apoptosis, were down-modulated by cocoa extract and (-)-epicatechin with p38 inhibition reaching up to 70%.ConclusionsOur results show that cocoa extract and (-)-epicatechin may exert a neuroprotective action by reducing ROS production and modulating MAPK activation.

Altered cell-matrix associated ADAM proteins in Alzheimer disease.

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, mem‐ brane‐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. J. Neurosci. Res. 59:680–684, 2000