Metallothionein‐I/II expression associates with the astrocyte DNA damage response and not Alzheimer‐type pathology in the aging brain

Abstract

Oxidative stress and oxidative DNA damage are early features of mild cognitive impairment and Alzheimer's disease (AD), occurring before the formation of classical AD neuropathology, and resulting from an imbalance between pro- and anti-oxidants. Astrocytes play a major neuroprotective role, producing high levels of anti-oxidants including metallothionein-I and -II (MT-I/II). In the present study we characterized the immunoreactive profile of MT-I/II in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) aging population-representative neuropathology cohort, and examined H O -modulation of MT transcription by human astrocytes. MT-I/II is primarily expressed by astrocytes in the aging brain, but is also associated with pyramidal neurons in a small proportion of cases. Astrocyte expression of MT-I/II does not correlate with Alzheimer-type pathology (Aβ plaques and neurofibrillary tangles) but does relate to astrocyte oxidative DNA damage (r = .312, p = .006) and the astrocyte response to oxidative DNA damage in vivo (r = .238, p = .04), and MT gene expression is significantly induced in human astrocytes response to oxidative stress in vitro (p = .01). In contrast, neuronal MT-I/II does not relate to oxidative DNA damage or the neuronal DNA damage response, but is significantly higher in cases with high levels of local tangle pathology (p = .007). As MT-I/II is neuroprotective against oxidative stress, modulation of MT-I/II expression is a potential therapeutic target to treat the onset and progression of cognitive impairment.

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

“…These antioxidant products suppress ROS/RNS and return microglia to the resting state (Min et al, 2006). Astrocytes also protect the brain against ischemia-associated oxidative stress by producing ROS scavenger metallothionein-II (Trendelenburg et al, 2002;Waller et al, 2018).…”

Downregulation of Metallothionein-2 Contributes to Oxaliplatin-induced Neuropathic Pain

“…Double immunostaining showed intense intracellular staining colocalized with the neuron marker NeuN in the spinal dorsal horn, suggesting that MT2 is almost exclusively expressed in the spinal horn neurons after oxaliplatin treatment. These data indicate a potential role for MT2 in the development of CIPN, and this possibility is not surprising given the evident involvement of MT2 in different physiological and protective CNS processes [22,24,35]. Fortunately, the locomotor function was not impaired in rats after either consecutive administration of oxaliplatin or genetic inhibition of MT2 via intrathecal siRNA injection.…”

Iron in Neurodegeneration – Cause or Consequence?

“…However, astroglia contain relatively small amounts of ferritin and iron (Mirza et al, 2000; Zecca et al, 2004; Bartzokis et al, 2007), yet in vitro studies in cultured astrocytes show that cultured astrocytes are surprisingly resistant to ferrous iron compared to neurons and oligodendrocytes, even though intracellular iron burden is comparable (Kress et al, 2002; Oshiro et al, 2008). Possibly this is due to an extensive antioxidative system including metallothioneins (Waller et al, 2018). Astroglia possess heme oxygenase-1, which has been shown to be neuroprotective in different models of PD by impeding oxidative stress (Xu et al, 2016; Yu et al, 2016), it has to be noted however that during the degradation of heme catalyzed by the enzyme, bio-reactive iron is released to participate in Fenton’s reaction (Cuadrado and Rojo, 2008).…”