Dataset Information

Brain-specific repression of AMPK?1 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 ? subunit exists in 2 isoforms: AMPK?1 and AMPK?2. Recent studies suggest a role of AMPK? 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 AMPK? isoforms in AD pathophysiology are not understood. Here, we showed distinct disruption of hippocampal AMPK? isoform expression patterns in postmortem human AD patients and AD model mice. We further investigated the effects of brain- and isoform-specific AMPK? repression on AD pathophysiology. We found that repression of AMPK?1 alleviated cognitive deficits and synaptic failure displayed in 2 separate lines of AD model mice. In contrast, AMPK?2 suppression did not alter AD pathophysiology. Using unbiased mass spectrometry-based proteomics analysis, we identified distinct patterns of protein expression associated with specific AMPK? isoform suppression in AD model mice. Further, AD-associated hyperphosphorylation of eukaryotic elongation factor 2 (eEF2) was blunted with selective AMPK?1 inhibition. Our findings reveal isoform-specific roles of AMPK? in AD pathophysiology, thus providing insights into potential therapeutic strategies for AD and related dementia syndromes.

SUBMITTER: Zimmermann HR

PROVIDER: S-EPMC7324210 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Zimmermann Helena R HR Yang Wenzhong W Kasica Nicole P NP Zhou Xueyan X Wang Xin X Beckelman Brenna C BC Lee Jingyun J Furdui Cristina M CM Keene C Dirk CD Ma Tao T

The Journal of clinical investigation 20200701 7

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 s ...[more]

PMID: 32213711

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Project description:Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer's disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10-8, β = 0.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.

Dataset Information

Brain-specific repression of AMPK?1 alleviates pathophysiology in Alzheimer's model mice.

Publications

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

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