Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership–AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.
Oxidative stress in Alzheimer’s disease (AD) is mediated, in part, by the loss of glutathione (GSH). Previous studies show that γ-glutamyl transpeptidase (GGT)-resistant GSH analog, Ψ-GSH, improves brain GSH levels, reduces oxidative stress markers in brains of APP/PS1 transgenic mice, a mouse model of AD, and attenuates early memory deficits in the APP/PS1 model. Herein, we examined whether Ψ-GSH can attenuate the disease progression when administered following the onset of AD-like pathology in vivo. Cohorts of APP/PS1 mice were administered Ψ-GSH for 2 months starting at 8 month or 12 months of age. We show that Ψ-GSH treatment reduces indices of oxidative stress in older mice by restoration of enzyme glyoxalase-1 (Glo-1) activity and reduces levels of insoluble Aβ. Quantitative neuropathological analyses show that Ψ-GSH treatment significantly reduces Aβ deposition and brain inflammation in APP/PS1 mice compared to vehicle-treated mice. More importantly, Ψ-GSH treatment attenuated the progressive loss of cortical TH+ afferents and the loss of TH+ neurons in the locus coeruleus (LC). Collectively, the results show that Ψ-GSH exhibits significant antioxidant activity in aged APP/PS1 mice and chronic Ψ-GSH treatment administered after the onset of AD pathology can reverse/slow further progression of AD-like pathology and neurodegeneration in vivo.
A modified Dimensional Change Card Sort (DCCS) task was used to test cognitive flexibility in adult cotton-top tamarins and children aged 19 months to 60 months. Subjects had to infer a rule from the experience of selecting between two cards to earn a reward, and the pairs of stimuli defined the rule (e.g., pick blue ones, not red ones, or pick trucks, not boats). Two different tests measured subjects’ ability to shift to a reversal of the rule (intradimensional shift) and to shift to a new rule defined by a dimension previously irrelevant (interdimensional shift). Both adult tamarins and children aged 49–60 months were able to learn the initial rule and switch to a reversal and to a rule based on a different dimension. In contrast, the two younger groups of children, aged 19–36 months and aged 37–48 months, could switch when a reversal was imposed but took significantly longer to learn a new rule on a former irrelevant dimension. Experiment 2 presented a wider set of novel stimuli which shared some features with the original set to further explore the basis of rule learning. The result was that tamarins and 52- to 60-month-old children both chose novel stimuli that fit the rule and had no a priori associative strength, suggesting a rule application not solely based on associative strength. Importantly, novel items introduced some risk for choice, and children showed themselves to be risk-averse, whereas tamarins were risk-prone within a novel context.
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