Bioenergetic mechanisms in astrocytes may contribute to amyloid plaque deposition and toxicity [Bioenergetics]

March 26th, 2015 by Fu, W., Shi, D., Westaway, D., Jhamandas, J. H.

Alzheimer′s disease (AD) is characterized neuropathologically by synaptic disruption, neuronal loss and deposition of amyloid beta (Aβ) protein in brain structures that are critical for memory and cognition. There is increasing appreciation, however, that astrocytes, which are the major non-neuronal glial cells, may play an important role in AD pathogenesis. Unlike neurons, astrocytes are resistant to Aβ cytotoxicity, which may in part be related to their greater reliance on glycolytic metabolism. Herein we show that in cultures of human fetal astrocytes, pharmacological inhibition or molecular down-regulation of a main enzymatic regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3), results in increased accumulation of Aβ within and around astrocytes and greater vulnerability of these cells to Aβ toxicity. We further investigated age-dependent changes in PFKFB3 and astrocytes in AD transgenic mice (TgCRND8) that over-express human Aβ. Using a combination of Western blotting and immunohistochemistry, we identified an increase in glial fibrillary acidic protein (GFAP) expression in astrocytes that paralleled escalation of Aβ plaque burden in TgCRND8 mice in an age-dependent manner. Furthermore, PFKFB3 expression also demonstrated an increase in these mice, albeit at a later age (9 months) than GFAP and Aβ. Immunohistochemical staining showed significant reactive astrogliosis surrounding Aβ plaques with increased PFKFB3 activity in 12-month old TgCRND8 mice, when AD pathology and behavioural deficits are fully manifest. These studies shed important light on the unique bioenergetic mechanisms within astrocytes that may contribute to the development of AD pathology.