Nicotine Alters Lysosomal Function of Astrocytes: An Implication for Exacerbation of Alzheimer Disease Pathology Viji Vijayan & Sarika Gupta Molecular Science Lab, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, INDIA 110067
Statement of the problem: Nicotine, an additive component of tobacco alters the incidence of Alzheimer Disease (AD). However the results are inconsistent warranting further research into this topic. Hypothesis and Aim: Astrocytes are a type of glial cell of the brain which regulate neuronal activity and synaptic transmission. Astrocyte differentiation is marked by increased expression of glial fibrillary acidic protein (GFAP), a type III intermediate filament. Our preliminary results showed that nicotine administration induces GFAP expression in brains of 5xFAD transgenic Alzheimer mouse model. We speculated whether this functional alteration of astrocyte function could be a reason for Abeta42 accumulation during AD. Materials and Methods: Cognitive function of wild type and 5xFAD mice was determined by Y-maze and Morris water maze tests. Changes in protein level in brain and Grade I C8D1A astrocyte cells were evaluated by immunohistochemistry, immunoblot, confocal analysis, ELISA and flow cytometry. Results: Presence of nicotine increased the endocytic activity of astrocytes towards Abeta42 as evidenced by uptake assay and increased expression of MHC-II, CD36 and CD11b. Though there were temporal changes in the expression status of lysosome associated proteins like cathepsin D, LAMP1 and CD68 in nicotine treated cultures as evidenced by immunoblot analysis; confocal microscopy revealed no colocalization of Abeta42 with lysosomes. With time we observed concentration of Abeta42 within cells and extrusion of Abeta in concentrated states. This release involved tetraspanin CD63 (LAMP3), an exosome marker since siRNA mediated downregulation of CD63 led to impaired release of Abeta42. Conclusions: Nicotine alters lysosomal function in astrocytes causing Abeta42 to concentrate in these glial cells which later gets extruded in concentrated form by a process involving CD63. Alteration of lysosomal function by nicotine is therefore an implication for amyloid pathology and loss of cognitive function during AD.
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