Michael Coleman is now Professor of Neuroscience in the Department of Clinical Neuroscience, University of Cambridge. Visit his page there for full details of his current research.
Michael studies basic mechanisms regulating axon survival. Age-related axon loss contributes to declining memory, senses, autonomic nervous system (bladder, gut, etc.) and motor function, leading to physical frailty. It also sets the biological context for age-related neurodegenerative disease.
Acetylcholinesterase (AChE), an important component of cholinergic synapses, colocalizes with amyloid-beta peptide (A beta) deposits of Alzheimer's brain. We report here that bovine brain AChE, as well as the human and mouse recombinant enzyme, accelerates amyloid formation from wild-type A beta and a mutant A beta peptide, which alone produces few amyloid-like fibrils. The action of AChE was independent of the subunit array of the enzyme, was not affected by edrophonium, an active site inhibitor, but it was affected by propidium, a peripheral anionic binding site ligand. Butyrylcholinesterase, an enzyme that lacks the peripheral site, did not affect amyloid formation. Furthermore, AChE is a potent amyloid-promoting factor when compared with other A beta-associated proteins. Thus, in addition to its role in cholinergic synapses, AChE may function by accelerating A beta formation and could play a role during amyloid deposition in Alzheimer's brain.
Asymmetric acetylcholinesterase (AChE) is anchored to the basal lamina (BL) of cholinergic synapses via its collagenic tail, yet the complement of matrix receptors involved in its attachment remains unknown. The development of a novel overlay technique has allowed us to identify two Torpedo BL components that bind asymmetric AChE: a polypeptide of approximately 140 kDa and a doublet of 195-215 kDa. These were found to stain metachromatically with Coomassie blue R-250, were solubilized by acetic acid, and were sensitive to collagenase treatment. Upon sequence analysis, the 140 kDa polypeptide yielded a characteristic collagenous motif. Another AChE-binding BL constituent, identified by overlay, corresponded to a heparan sulfate proteoglycan. Lastly, we established that this proteoglycan, but not the collagenous proteins, interacted with at least one heparin binding domain of the collagenic tail of AChE. Our results indicate that at least two BL receptors are likely to exist for asymmetric AChE in Torpedo electric organ.
BB rats develop autoimmune diabetes mellitus at a high frequency. A key factor in the development of the disease is an autosomal recessive mutation determining peripheral T cell lymphocytopenia. Previous studies have suggested that the lymphopenia could be caused by increased cell death. Here we demonstrate that the lyp mutation dramatically reduces the in vitro lifespan of the TCRhi single-positive thymocytes and peripheral T cells, without abolishing their capacity to proliferate. The reduced lifespan is due to an increased rate of apoptosis, and is detected in single-positive thymocytes displaying characteristics of cells which have undergone positive selection. The cell death defect does not affect the in vitro lifespan of peripheral B cells. Interestingly, stimulation can rescue peripheral lyp/lyp T cells from immediate cell death. We propose that the lymphopenia mutation prevents the accumulation of a normal T cell pool, including regulatory subsets, without preventing the activation and proliferation of reactive T cells, thereby creating conditions appropriate for the development of uncontrolled autoimmune responses.