Changes in Intracellular Calcium and Glutathione in Astrocytes as the Primary Mechanism of Amyloid Neurotoxicity

Abstract

Although the accumulation of the neurotoxic peptide beta amyloid (betaA) in the CNS is a hallmark of Alzheimer's disease, the mechanism of betaA neurotoxicity remains controversial. In cultures of mixed neurons and astrocytes, we found that both the full-length peptide betaA (1-42) and the neurotoxic fragment (25-35) caused sporadic cytoplasmic calcium [intracellular calcium ([Ca2+]c)] signals in astrocytes that continued for hours, whereas adjacent neurons were completely unaffected. Nevertheless, after 24 hr, although astrocyte cell death was marginally increased, approximately 50% of the neurons had died. The [Ca2+]c signal was entirely dependent on Ca2+ influx and was blocked by zinc and by clioquinol, a heavy-metal chelator that is neuroprotective in models of Alzheimer's disease. Neuronal death was associated with Ca2+-dependent glutathione depletion in both astrocytes and neurons. Thus, astrocytes appear to be the primary target of betaA, whereas the neurotoxicity reflects the neuronal dependence on astrocytes for antioxidant support.

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

“…A previous study showed decreased levels of mitochondrial Ca 2+ under pathological conditions (Granatiero et al., 2015). Discordant results have been reported regarding the effects of Aβ on cellular and mitochondrial calcium, with studies showing data both consistent and contradictory with our findings (Abramov, Canevari & Duchen, 2003, 2004). …”

Astrocytes in Alzheimer's Disease

“…169 170,171 The abnormal, spontaneous Ca 2ϩ oscillations and Ca 2ϩ waves were also observed in vivo in astrocytes associated with neuritic plaques. 172 Furthermore, astrocytes in A␤ overexpressing transgenic mice demonstrated increased coupling in neocortical regions and had elevated expression of AMPA/kainate glutamate receptors and glutamate transporters.…”

Astroglia in dementia and Alzheimer's disease

“…52 In mixed astroglial-neuronal cultures b-amyloid peptide (Ab 1-42) and its toxic fragment (Ab 25-35) provoked sporadic increases and/or oscillations in cytosolic calcium [Ca 2 þ ] i , which lasted for many hours. 53 These [Ca 2 þ ] i responses were observed solely in astrocytes and never in neurones and were generated by Ca 2 þ influx from extracellular space, most likely through transmembrane channels formed by Ab proteins. Importantly, astroglial [Ca 2 þ ] i fluctuations were somehow linked to neuronal death, which occurred 24 h after Ab treatment; inhibition of Ca 2 þ influx had a clear neuroprotective effect.…”

“…Importantly, astroglial [Ca 2 þ ] i fluctuations were somehow linked to neuronal death, which occurred 24 h after Ab treatment; inhibition of Ca 2 þ influx had a clear neuroprotective effect. 53 In the AD human tissue the main astroglial reaction found hitherto is represented by prominent astrogliosis, mostly observed in the cells surrounding amyloid plaques. 54 Importantly, activated astrocytes are capable of accumulating large amounts of Ab; 55 the later being taken up by astrocytes in association with neuronal debris.…”