Abstract
Alzheimer disease (AD) is characterized neuropathologically by synaptic disruption, neuronal loss, and deposition of amyloid β (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. Here 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 overexpress human Aβ. Using a combination of Western blotting and immunohistochemistry, we identified an increase in glial fibrillary acidic protein expression in astrocytes that paralleled the escalation of the Aβ plaque burden in TgCRND8 mice in an age-dependent manner. Furthermore, PFKFB3 expression also demonstrated an increase in these mice, although 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, an age when AD pathology and behavioral deficits are fully manifested. These studies shed light on the unique bioenergetic mechanisms within astrocytes that may contribute to the development of AD pathology.
Highlights
Glycolysis in astrocytes may govern amyloid accumulation and cytotoxicity
Neurons express low levels of PFKFB3 but higher levels of APC/ C-Cdh1 activity. These distinctions result in astrocytes functioning at a high glycolysis rate and neurons being extremely sensitive to energy depletion and degeneration [22]
Astrocytes in human fetal astrocytes (HFAs) cultures that became reactive showed morphological cellular changes and increased GFAP staining after exposure to either A or an impairment of glucose metabolism with application of glycolytic inhibitors (Fig 3d)
Summary
Glycolysis in astrocytes may govern amyloid accumulation and cytotoxicity. Results: Inhibiting astrocytic PFKFB3 results in an accumulation of amyloid protein and vulnerability to A cytotoxicity. Immunohistochemical staining showed significant reactive astrogliosis surrounding A plaques with increased PFKFB3 activity in 12-month-old TgCRND8 mice, an age when AD pathology and behavioral deficits are fully manifested These studies shed light on the unique bioenergetic mechanisms within astrocytes that may contribute to the development of AD pathology. A comparison of rat neurons and astrocytes reveals a differential bioenergetic response between the two cell types to experimental stimuli (such as nitric oxide or glutamate) that induce cellular stress [16, 17]. On the basis of these observations, we hypothesized that, in astrocytes, impairment of bioenergetic mechanisms involving enzyme PFKFB3 renders these cells vulnerable to A toxicity and promotes A accumulation and plaque formation, a key feature of AD pathogenesis. We sought to examine the levels of PFKFB3 in TgCRND8 transgenic mice (expressing a mutant human amyloid precursor protein (APP)) versus age-matched wild-type mice and to correlate such alterations with age-dependent increases in A plaques observed in TgCRND8 mice
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