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

Abstract

Figure 1. Expression of AMPKα isoforms is dysregulated in AD hippocampus. (A) Hippocampus (Hip) lysate from sAD patients showed increased AMPKα1 and decreased AMPKα2 levels as compared with those of age-matched controls (CT). n = 10 with up to 4 technical replicates. *P = 0.0119; **P = 0.0014, unpaired t test. (B) Representative images of AMPKα isoform dysregulation in area CA1 of hippocampus in AD and age-matched control patients. Scale bar: 50 μm. Immunohistochemical experiments were replicated independently 3 times. (C) AMPKα isoform expression was unaffected in cerebellum (CER) samples from AD patients. n = 5 with up to 3 technical replicates. P = 0.8457 for AMPKα1; P = 0.9870 for AMPKα2, unpaired t test. (D) Hippocampal lysate from LBD patients had unaffected AMPKα isoform levels. n = 4 for control; n = 3 for LBD with 1 technical replicate. P = 0.9146 for AMPKα1; P = 0.5635 for AMPKα2, unpaired t test. (E) Levels of AMPK isoforms were unaltered in hippocampal tissue from FTD patients. n = 8 for control with 1 technical replicate; n = 5 for FTD with up to 3 technical replicates. P = 0.9283 for AMPKα1; P = 0.335 for AMPKα2, unpaired t test. (F) AMPKα1 levels were significantly increased in cortical lysates from FAD patients, while AMPKα2 levels were unaffected. n = 5 with 4 technical replicates. **P = 0.0060 for AMPKα1; P = 0.9412 for AMPKα2, unpaired t test. (G) AMPKα1 levels were significantly increased in hippocampal lysates from Tg19959 AD model mice compared with WT controls. AMPKα2 levels were unaffected. n = 7 with up to 2 technical replicates. **P = 0.0023 for AMPKα1; P = 0.9094 for AMPKα2, unpaired t test. 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. (H) Immunofluorescent labeling of DAPI (blue) and AMPKα1 (red) distribution in area CA1 mouse hippocampal slices. n = 3. Scale bar: 200 μm.

Protein expression alteration in hippocampus upon genetic repression of AMPKα isoforms

“…Second, similar to the results from hippocampus, most altered proteins in PFC are uniquely regulated by suppression of either AMPKα1 or α2 (but not both). The results are consistent with recent studies indicating isoform-specific roles of AMPKα in neuronal plasticity, cognitive function, and neurodegenerative diseases(Yang et al, 2020;Zimmermann et al, 2020). As discussed above, AMPK plays a central role in regulating cellular energy homeostasis, disruption of which is indicated many…”

“…Notably, one of the top proteins that were uniquely upregulated in hippocampi of the AMPKα1 cKO mice is NEDD8-activating enzyme E1 regulatory subunit (Q8VBW6), which can bind to the amyloid precursor protein and is considered to play a role in AD pathogenesis (Chen, McPhie, Hirschberg, & Neve, 2000;Gong & Yeh, 1999). Such finding is interesting in light of our recent studies suggesting a critical role of AMPKα1 dysregulation in AD pathophysiology (Zimmermann et al, 2020). It is also worth mentioning another upregulated protein in the AMPKα1 cKO condition: Polyadenylate-binding protein 1 (PABP1, P29341).…”

“…For instance, suppression of AMPKα2 but not AMPKα1 isoform in mice results in cognitive impairment and synaptic failure (Yang, Zhou, Zimmermann, & Ma, 2020). Moreover, expression of AMPKα isoforms is dysregulated in brains of AD patients and AD animal models, and genetic restoration of brain AMPKα1 level alleviates multiple aspects of pathophysiology in AD model mice (Zimmermann et al, 2020).…”

Isoform-specific roles of AMPK catalytic α subunits in Alzheimer’s disease

“…However, prior studies demonstrated AMPK activation, measured by Thr172 phosphorylation, in cerebral neurons of multiple tauopathies, including Pick's disease and progressive supranuclear palsy (6). Since Zimmermann et al (17) did not determine AMPK activation/phosphorylation in the human brain, there is a possibility that phosphorylation, rather than expressional change, may activate AMPK in FTD or DLB samples. Nevertheless, the isoform-specific dysregulation of AMPK in postmortem AD brain tissue raised the important question of how AMP-Kα1/2 is differentially regulated in AD.…”

Adenosine Metabolism in the Cerebral Cortex from Several Mice Models during Aging

“…The AMPK is a serine/threonine kinase with a key role as an energy sensor in a wide variety of tissues. It coordinates cell growth, autophagy, and metabolism [ 48 , 49 , 50 , 51 ], and appears to be involved in the pathophysiology of AD [ 52 ]. AMPK is a trimer, with α-, β-, and γ-subunits.…”