Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice
Helena R. Zimmermann, … , C. Dirk Keene, Tao Ma
Helena R. Zimmermann, … , C. Dirk Keene, Tao Ma
Published March 26, 2020
Citation Information: J Clin Invest. 2020;130(7):3511-3527. https://doi.org/10.1172/JCI133982.
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Research Article Aging Neuroscience

Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice

Abstract

AMPK is a key regulator at the molecular level for maintaining energy metabolism homeostasis. Mammalian AMPK is a heterotrimeric complex, and its catalytic α subunit exists in 2 isoforms: AMPKα1 and AMPKα2. Recent studies suggest a role of AMPKα overactivation in Alzheimer’s disease–associated (AD-associated) synaptic failure. However, whether AD-associated dementia can be improved by targeting AMPK remains unclear, and roles of AMPKα isoforms in AD pathophysiology are not understood. Here, we showed distinct disruption of hippocampal AMPKα isoform expression patterns in postmortem human AD patients and AD model mice. We further investigated the effects of brain- and isoform-specific AMPKα repression on AD pathophysiology. We found that repression of AMPKα1 alleviated cognitive deficits and synaptic failure displayed in 2 separate lines of AD model mice. In contrast, AMPKα2 suppression did not alter AD pathophysiology. Using unbiased mass spectrometry–based proteomics analysis, we identified distinct patterns of protein expression associated with specific AMPKα isoform suppression in AD model mice. Further, AD-associated hyperphosphorylation of eukaryotic elongation factor 2 (eEF2) was blunted with selective AMPKα1 inhibition. Our findings reveal isoform-specific roles of AMPKα in AD pathophysiology, thus providing insights into potential therapeutic strategies for AD and related dementia syndromes.

Authors

Helena R. Zimmermann, Wenzhong Yang, Nicole P. Kasica, Xueyan Zhou, Xin Wang, Brenna C. Beckelman, Jingyun Lee, Cristina M. Furdui, C. Dirk Keene, Tao Ma

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Figure 2

Brain-specific suppression of AMPKα1 alleviates learning and memory defects in Tg19959 AD model mice.

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Brain-specific suppression of AMPKα1 alleviates learning and memory defe...
(A) Brain-specific genetic reduction of AMPKα1 and AMPKα2 in Tg19959 AD model mice. Noncongruous WT, Tg19959 (Tg), AMPKα1+/–/Tg19959 (α1/Tg), AMPKα2+/–/Tg19959 (α2/Tg). n = 10, 10, 6, 7; up to 3 technical replicates. For AMPK α1: WT versus Tg, *P = 0.0212; WT versus α2/Tg, **P = 0.0029; Tg versus α1/Tg, ***P = 0.0130; α1/Tg versus α2/Tg, #P = 0.0016. One-way ANOVA with Tukey’s post hoc test, F = 8.218. For AMPKα2: WT versus α2/Τg, ##P = 0.005; Tg versus α2/Tg, ###P = 0.043; α1/Tg versus α2/Tg, †P = 0.007. One-way ANOVA with Tukey’s post hoc test. F = 7.585. (B) Representative H&E stain of hippocampal structure. n = 3. Scale bar: 50 μm. (C) Percentage of time spent in the periphery for the OF test. n = 25, 21, 17, 14, 19, and 13. (D) Percentage of time spent with familiar (white) and novel (purple) objects in the NOR task during the testing phase. Preference of less than 50% indicates cognitive impairment. n = 19, 13, 10, 9, 10, and 8. Statistical preference for novel or familiar object: WT, *P < 0.0001; Tg, P = 0.5523; α1/cre, **P = 0.0004; α1/Tg, ***P = 0.0008; α2/cre, #P = 0.0465; α2/Tg, P = 0.1497, unpaired t test. (E) Escape latency (s) over 5 days of training in the hidden platform MWM. Four trials/day, 5 days. n = 19, 17, 13, 17, 19, and 13. WT versus α1/Tg, *P = 0.0256; Tg versus α1/Tg, **P = 0.0094; α1/Tg versus α2/Tg, ***P = 0.0009; ****P < 0.0001, 1-way ANOVA with Tukey’s post hoc test. F = 18.16. (F) Percentage of time spent in the target quadrant during probe trial phase of MWM task. WT versus α2/Tg, *P = 0.0186; WT versus Tg, **P = 0.0027, 1-way ANOVA with Tukey’s post hoc test. F = 4.525. Box-and-whisker plots represent the interquartile range, with the line across the box indicating the median. Whiskers show the highest and lowest values detected.