Alzheimer Disease: Grierson AJ

De Vos KJ, Grierson AJ, Ackerley S, Miller CC. · MRC Center for Neurodegeneration Research, Institute of Psychiatry, King's College, London SE5 8AF, United Kingdom. · Annu Rev Neurosci. · Pubmed #18558852 No free full text.

Abstract: Many major human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), display axonal pathologies including abnormal accumulations of proteins and organelles. Such pathologies highlight damage to the axon as part of the pathogenic process and, in particular, damage to transport of cargoes through axons. Indeed, we now know that disruption of axonal transport is an early and perhaps causative event in many of these diseases. Here, we review the role of axonal transport in neurodegenerative disease.

Connell JW, Rodriguez-Martin T, Gibb GM, Kahn NM, Grierson AJ, Hanger DP, Revesz T, Lantos PL, Anderton BH, Gallo JM. · Department of Neuroscience, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK. · Brain Res Mol Brain Res. · Pubmed #15950767 No free full text.

Abstract: A number of neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by intraneuronal accumulation of the tau protein. Some forms of FTDP-17 are caused by mutations in the tau gene affecting exon 10 splicing. Therefore, dysregulation of tau pre-mRNA splicing may be a contributing factor to sporadic tauopathies. To address this question, we devised a real-time RT-PCR strategy based on the use of a single fluorogenic probe to evaluate the ratio between tau isoforms containing or lacking exon 10 (4R/3R ratio) in post-mortem brain samples. We found a two- to six-fold increase in the 4R/3R ratio in cases of FTDP-17 linked to a splice site mutation, hence confirming the validity of the strategy. The difference in the 4R/3R ratio in the superior temporal and superior frontal gyri between AD and control brains was not statistically significant. Similarly, there was no significant difference in the 4R/3R ratio between Pick's disease cases and controls, indicating that the predominance of tau3R protein in PiD reflects post-translational modifications of specific isoforms. This study indicates that post-translational events are likely to be the main factors controlling tau isoform composition in sporadic tauopathies and highlights the benefit of quantitative RT-PCR in the assessment of splicing abnormalities in tauopathies.

Standen CL, Brownlees J, Grierson AJ, Kesavapany S, Lau KF, McLoughlin DM, Miller CC. · Department of Neuroscience, Institute of Psychiatry, Kings College, London, UK. · J Neurochem. · Pubmed #11146006 No free full text.

Abstract: Threonine(668) (thr(668)) within the carboxy-terminus of the Alzheimer's disease amyloid precursor protein (APP) is a known in vivo phosphorylation site. Phosphorylation of APPthr(668) is believed to regulate APP function and metabolism. Thr(668) precedes a proline, which suggests that it is targeted for phosphorylation by proline-directed kinase(s). We have investigated the ability of four major neuronally active proline-directed kinases, cyclin dependent protein kinase-5, glycogen synthase kinase-3 beta, p42 mitogen-activated protein kinase and stress-activated protein kinase-1b, to phosphorylate APPthr(668) and report here that SAPK1b induces robust phosphorylation of this site both in vitro and in vivo. This finding provides a molecular framework to link cellular stresses with APP metabolism in both normal and disease states.