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Abstract
A small molecule named ISRIB has recently been described to enhance memory in rodents. In this study we aimed to test whether ISRIB would reverse learning and memory deficits in the J20 mouse model of human amyloid precursor protein (hAPP) overexpression, a model that simulates many aspects of Alzheimer’s disease in which memory deficits are a hallmark feature. We did not observe a significant rescue effect with ISRIB treatment on spatial learning and memory as assessed in the Morris water maze in J20 mice. We also did not observe a significant enhancement of spatial learning or memory in nontransgenic mice with ISRIB treatment, although a trend emerged for memory enhancement in one cohort of mice. Future preclinical studies with ISRIB would benefit from additional robust markers of target engagement in the brain.
Highlights
The prevalence of Alzheimer’s disease (AD) is increasing as the human population ages, and treatments that slow or reverse the disease are urgently needed (Alzheimer’s Association, 2015)
We noted a very weak band at approximately 50kD in the brain homogenates that appeared to be a nonspecific background band, but we quantified this band on the possibility that it represented a uniquely post-translationally modified ATF4. The levels of this protein were not different between NTG and J20 mice in either cortex or dentate gyrus in all 3 age groups (Fig. 1B; unpaired t test, p > 0.05). These results suggest that the integrated stress response (ISR) is not significantly elevated in human amyloid precursor protein (hAPP)-J20 mice or in nontransgenic mice
We found that a minimal volume of 50% DMSO/ 50% polyethyleneglycol (PEG) was sufficient to dissolve and deliver the hydrophobic ISRIB compound at a 10-fold greater dose (2.5 mpk) than what could be achieved with 1% DMSO/saline during the pilot Morris water maze (MWM) experiment
Summary
The prevalence of Alzheimer’s disease (AD) is increasing as the human population ages, and treatments that slow or reverse the disease are urgently needed (Alzheimer’s Association, 2015). In AD, loss of the ability to form new memories, and eventually to recall long-term memories, is a defining clinical feature. While the causes of AD remain a focus of intense investigation, treatments that can enhance the brain’s innate ability to form and retrieve memories, or that counteract the mechanisms the lead to memory loss, could offer an immediate benefit to the millions of people who currently suffer from this disease. ISRIB binds to and activates the guanine nucleotide exchange factor eIF2B (elongation initiation factor 2 B), which in turn relieves inhibition of protein translation caused by phosphorylation of the alpha subunit of initiation factor 2 (eIF2α) (Sidrauski et al, 2013; Sekine et al, 2015; Sidrauski et al, 2015a; Sidrauski et al, 2015b).
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