Role of Amyloid-β in modulating gap junction protein Cx43

Vasan, Lakshmy (2018) Role of Amyloid-β in modulating gap junction protein Cx43. Masters thesis, Indian Institute of Science Education and Research Kolkata.

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Abstract

Cellular communication facilitated by the gap junction channels play an important role in maintaining the cellular homeostasis. Gap junction channels are formed of a highly diverse protein family comprising of connexin proteins. Different connexin proteins span the cell membrane of different cell types of which connexin 43 (Cx43) is the predominant connexin expressed in astrocyte membranes and plays an important role in maintaining brain homeostasis. Connexin channels at the cell surface are present either as gap junctions that connect the cytoplasm of two adjacent cells or as hemichannels that connect the cell cytoplasm to the extracellular matrix. Several studies have suggested that connexin levels are altered in Alzheimers’s disease, a progressive neurodegenerative disease that mostly affects the elderly population in our society. Studies in murine models have shown increased immunoreactivity of Cx43 in reactive astrocytes and microglia surrounding the amyloid-β (Aβ) plaques, the major pathological hallmark characterising all AD brains. Recently, Aβ25-35, the toxic fragment of Aβ has been reported to play a role in the elevation of hemichannels in glial cells, where increased hemichannel activity has been shown to release ATP, glutamate etc in abundance leading to neurotoxicity. The overall aim of the present work is to investigate the underlying molecular mechanisms by which Aβ modulates Cx43 function in mouse primary astrocytes. The preliminary results show that the Cx43 levels are altered upon Aβ25-35 treatment. Immunofluorescence labelling followed by microscopy indicate an elevated puncta size of Cx43 when treated with Aβ25-35. Aβ25-35 treated cells show an elevated hemichannel activity in the functional assay whereas intercellular the gap junctional communication is disrupted. Surface distribution of connexin43 is currently under investigation. The results obtained so far suggest that increased Aβ levels can modulate Cx43 function by regulating its expression and cellular distribution.

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