Hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function

Abstract

Loss of brain glutathione has been associated with cognitive decline and neuronal death during aging and neurodegenerative diseases. However, whether decreased glutathione precedes or follows neuronal dysfunction has not been unambiguously elucidated. Previous attempts to address this issue were approached by fully eliminating glutathione, a strategy causing abrupt lethality or premature neuronal death that led to multiple interpretations. To overcome this drawback, here we aimed to moderately decrease glutathione content by genetically knocking down the rate-limiting enzyme of glutathione biosynthesis in mouse neurons in vivo. Biochemical and morphological analyses of the brain revealed a modest glutathione decrease and redox stress throughout the hippocampus, although neuronal dendrite disruption and glial activation was confined to the hippocampal CA1 layer. Furthermore, the behavioral characterization exhibited signs consistent with cognitive impairment. These results indicate that the hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function.

Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper

“…Further analysis showed that the decreases in GSH were not secondary to tissue atrophy. Interestingly, two recent studies in mice that used knockdown of the catalytic subunit of glutamate cysteine ligase, the rate limiting enzyme for GSH biosynthesis in all neurons [ 66 ] or only forebrain neurons [ 67 ], to specifically reduce neuronal GSH levels, showed an enhanced, age-dependent development of cognitive deficits relative to control animals, supporting the idea that GSH loss contributes to cognitive impairments in aging and AD. Importantly, in the former study [ 66 ], the decrease in GSH levels in the hippocampus was modest but comparable to that seen in MCI and AD subjects [ 65 ].…”

“…Interestingly, two recent studies in mice that used knockdown of the catalytic subunit of glutamate cysteine ligase, the rate limiting enzyme for GSH biosynthesis in all neurons [ 66 ] or only forebrain neurons [ 67 ], to specifically reduce neuronal GSH levels, showed an enhanced, age-dependent development of cognitive deficits relative to control animals, supporting the idea that GSH loss contributes to cognitive impairments in aging and AD. Importantly, in the former study [ 66 ], the decrease in GSH levels in the hippocampus was modest but comparable to that seen in MCI and AD subjects [ 65 ]. Thus, age- and AD-dependent decreases in GSH levels may make the elderly particularly susceptible to damage associated with the age- and AD-dependent increases in the concentrations of iron and copper in the brain [ 14 , 25 ] and thereby initiate a feed forward cycle of cell damage and death.…”

Mitochondrial Bioenergetics in Brain Following Ozone Exposure in Rats Maintained on Coconut, Fish and Olive Oil-Rich Diets

“…Furthermore, the activity levels corroborate the TAS measures, but only in this region. Recently, it has been demonstrated that HIP requires large pools of glutathione to sustain dendritic integrity [62]. Therefore, it is plausible that glutathione may be the dominate antioxidant in the HIP, thus driving the measure of TAS for that region.…”

Therapeutic potential of glutathione-enhancers in stress-related psychopathologies

“…Unlike other cellular antioxidants that target a specific type of ROS, GSH is an endogenous compound that protects against multiple oxidative insults (Mizui, Kinouchi et al 1992;Dringen, Pawlowski et al 2005). Notably, neurons require high levels of GSH to counteract oxidative stress and maintain proper brain structural integrity and cognitive function (Fernandez-Fernandez, Bobo-Jimenez et al 2018).…”