Abstract
Understanding the molecular mechanisms underlying age-associated cognitive impairments will not only contribute to our general knowledge about “aging” biology, but also provide insights for more effective strategies to prevent and improve the quality of life for both normal aging and pathological aging such as Alzheimer’s disease (AD). Here we first assessed and compared the performance of cognition and synaptic plasticity in young (3–5-month old) and aged c57BL/6J mice (19–21 months old). Findings from behavioral tests demonstrated that old mice, compared to young mice, displayed impairments in spatial learning/memory, working memory, and behavioral flexibility. Further, synaptic electrophysiology experiments on hippocampal slices revealed that the early form of long-term potentiation (LTP, a synaptic model for memory formation) was inhibited in old mice. At the molecular level, biochemical assays on the hippocampus showed dysregulation of signaling pathways controlling protein synthesis capacity including: up-regulation of AKT-mTORC1-p70S6K signaling, which is associated with translation of terminal oligopyrimidine (TOP) class of mRNAs that encode translational machinery; hyper-phosphorylation of mRNA translational elongation factor 2 (eEF2) and its upstream regulator AMP-activated protein kinase (AMPK), indicating repression of general protein synthesis. Moreover, young and old mice exhibited similar brain levels of translational initiation factor 2α (eIF2α) phosphorylation, which is known to be increased in AD and linked to the disease pathophysiology. Thus, our data provide evidence at the molecular level to highlight the similarity and difference between normal and pathological aging, which may contribute to future studies on diagnostic/prognostic biomarkers for aging-related dementia syndromes.
Highlights
Certain aspects of cognitive abilities, such as learning and memory, decline with normal aging (Burke and Barnes, 2006; Klencklen et al, 2012)
To assess whether the impaired performance of old mice on hidden platform Morris Water Maze (MWM) could be attributed to memory-independent effects such as vision and swimming ability, we further tested the mice on the visible platform task, and did not observe differences between the young and old groups of mice (Supplementary Figure S1A)
We found that, compared to young mice, brain levels of eEF2 phosphorylation (Thr56 site) were markedly increased (Figure 2F), which is associated with a repressed capacity for general protein synthesis (Taha et al, 2013)
Summary
Certain aspects of cognitive abilities, such as learning and memory, decline with normal aging (Burke and Barnes, 2006; Klencklen et al, 2012). The mammalian target of rapamycin complex 1 (mTORC1) controls cap-dependent translation initiation via its downstream target eukaryotic initiation 4E binding protein 1 (4EBP1), and synthesis of translational apparatus (e.g., ribosomal proteins) encoded by terminal oligopyrimidine (TOP) class of mRNAs (Meyuhas, 2000; Tsokas et al, 2007; Hoeffer and Klann, 2010) Another molecular mechanism of mRNA translation regulation involves phosphorylation (by one of the four kinases including PERK, PKR, GCN2, and HRI) on the α subunit of initiation factor 2 (eIF2α), leading to inhibition of translation initiation and general protein synthesis (Wek et al, 2006; Trinh and Klann, 2013). Potential upstream regulators of eEF2K-eEF2 includes mTORC1, and AMP-activated protein kinase (AMPK), a central molecular sensor to maintain cellular energy homeostasis (Hardie et al, 2012; Taha et al, 2013, Kenney et al, 2014)
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