| Autor: |
Barbato C; Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Campus A. Buzzati-Traverso, via E. Ramarini 32, Monterotondo, RM, Italy.; Department of Sense Organs, IBBC, CNR, University Sapienza Rome, Viale del Policlinico 155, 00161, Rome, Italy., Giacovazzo G; Preclinical Neuroscience, European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, via del Fosso di Fiorano 64, 00143, Rome, Italy., Albiero F; Institute of Cell Biology and Neurobiology, National Research Council (CNR), Via Fosso del Fiorano 64, 000143, Rome, Italy., Scardigli R; Institute of Translational Pharmacology, National Research Council (CNR), Via Fosso del Cavaliere 100, 00133, Rome, Italy.; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161, Rome, Italy., Scopa C; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161, Rome, Italy., Ciotti MT; Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Campus A. Buzzati-Traverso, via E. Ramarini 32, Monterotondo, RM, Italy., Strimpakos G; Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Campus A. Buzzati-Traverso, via E. Ramarini 32, Monterotondo, RM, Italy., Coccurello R; Preclinical Neuroscience, European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, via del Fosso di Fiorano 64, 00143, Rome, Italy.; Institute for Complex System (ISC), National Research Council (CNR), via dei Taurini 19, 00185, Rome, Italy., Ruberti F; Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Campus A. Buzzati-Traverso, via E. Ramarini 32, Monterotondo, RM, Italy. francesca.ruberti@cnr.it. |
| Abstrakt: |
MicroRNAs have emerged as regulators of brain development and function. Reduction of miR-101 expression has been reported in rodent hippocampus during ageing, in the brain of Alzheimer's disease (AD) patients and in AD animal models. In this study, we investigated the behavioral and molecular consequences of inhibition of endogenous miR-101 in 4-5-month-old C57BL/6J mice, infused with lentiviral particles expressing a miR-101 sponge (pLSyn-miR-101 sponge) in the CA1 field of the hippocampus. The sponge-infected mouse model showed cognitive impairment. The pLSyn-miR-101 sponge-infected mice were unable to discriminate either a novel object location or a novel object as assessed by object place recognition (OPR) and novel object recognition (NOR) tasks, respectively. Moreover, the sponge-infected mice evaluated for contextual memory in inhibitory avoidance task showed shorter retention latency compared to control pLSyn mice. These cognitive impairment features were associated with increased hippocampal expression of relevant miR-101 target genes, amyloid precursor protein (APP), RanBP9 and Rab5 and overproduction of amyloid beta (Aβ) 42 levels, the more toxic species of Aβ peptide. Notably, phosphorylation-dependent AMP-activated protein kinase (AMPK) hyperactivation is associated with AD pathology and age-dependent memory decline, and we found AMPK hyperphosphorylation in the hippocampus of pLSyn-miR-101 sponge mice. This study demonstrates that mimicking age-associated loss of miR-101 in hippocampal neurons induces cognitive decline and modulation of AD-related genes in mice. |
Full text from SpringerLink