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AMPK is a key regulator at the molecular level for maintaining energy metabolism homeostasis. Mammalian AMPK is a heterotrimeric complex, and its catalytic [alpha] subunit exists in 2 isoforms: AMPK[alpha]1 and AMPK[alpha]2. Recent studies suggest a role of AMPK[alpha] 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[alpha] isoforms in AD pathophysiology are not understood. Here, we showed distinct disruption of hippocampal AMPK[alpha] isoform expression patterns in postmortem human AD patients and AD model mice. We further investigated the effects of brain- and isoform-specific AMPK[alpha] repression on AD pathophysiology. We found that repression of AMPK[alpha]1 alleviated cognitive deficits and synaptic failure displayed in 2 separate lines of AD model mice. In contrast, AMPK[alpha]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[alpha] isoform suppression in AD model mice. Further, AD-associated hyperphosphorylation of eukaryotic elongation factor 2 (eEF2) was blunted with selective AMPK[alpha]1 inhibition. Our findings reveal isoform-specific roles of AMPK[alpha] in AD pathophysiology, thus providing insights into potential therapeutic strategies for AD and related dementia syndromes., Introduction Alzheimer's disease (AD) is the most common form of dementia and has become a global threat to public health. Currently, there is no effective intervention for curing AD or [...]

Molecular signaling mechanisms underlying Alzheimer's disease (AD) remain unclear. Maintenance of memory and synaptic plasticity depend on de novo protein synthesis, dysregulation of which is implicated in AD. Recent studies showed AD-associated hyperphosphorylation of mRNA translation factor eukaryotic elongation factor 2 (eEF2), which results in inhibition of protein synthesis. We tested to determine whether suppression of eEF2 phosphorylation could improve protein synthesis capacity and AD-associated cognitive and synaptic impairments. Genetic reduction of the eEF2 kinase (eEF2K) in 2 AD mouse models suppressed AD-associated eEF2 hyperphosphorylation and improved memory deficits and hippocampal long-term potentiation (LTP) impairments without altering brain amyloid [beta] (A[beta]) pathology. Furthermore, eEF2K reduction alleviated ADassociated defects in dendritic spine morphology, postsynaptic density formation, de novo protein synthesis, and dendritic polyribosome assembly. Our results link eEF2K/eEF2 signaling dysregulation to AD pathophysiology and therefore offer a feasible therapeutic target., Introduction The molecular signaling mechanisms underlying Alzheimer's disease (AD) pathophysiology remain elusive, hindering the development of effective treatments. AD is characterized by profound memory loss and synaptic failure (1). A [...]

2‐Hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) is an experimental therapy for Niemann‐Pick disease type C (NPC) that reduced neuronal cholesterol and ganglioside storage, reduced Purkinje cell death, and increased lifespan in npc1−/− mice and NPC1 cats. In this study, tissue distribution was investigated in normal cats that received a single 120‐mg dose of [14C]‐HP‐β‐CD (approximately 200 μCi/cat) via the cerebellomedullary cistern (CBMC) and lumbar cistern. One cat was euthanized at each of various time points up to 24 hours postdose for subsequent processing and quantitative whole‐body autoradiographic analysis. HP‐β‐CD‐derived radioactivity absorbed from the CBMC was widely distributed to cat tissues; most tissues were observed to have reached their highest concentration at 1 hour postdose. HP‐β‐CD‐derived radioactivity penetrated into the deeper parts of the central nervous system with the highest concentration at 4 hours (403 μg Eq/g or 0.28 mM) and remained high (49.7 μg Eq/g or 0.03 mM) at 24 hours. The relatively long half‐life (11‐30 hours) in cerebral ventricles and the subarachnoid space surrounding the brain and spinal cord might contribute to the efficacy of HP‐β‐CD in NPC1 cats. Other tissues with high concentrations of radioactivity were nasal turbinates, pituitary gland, and urinary bladder, while relatively low concentrations were observed in blood and bile. [ABSTRACT FROM AUTHOR]