Increased hippocampal accumulation of autophagosomes predicts short-term recognition memory impairment in aged mice |
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Authors: | Virawudh Soontornniyomkij Victoria B Risbrough Jared W Young Benchawanna Soontornniyomkij Dilip V Jeste Cristian L Achim |
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Institution: | (1) Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603, USA;(2) Department of Psychiatry, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603, USA |
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Abstract: | Constitutive macroautophagy involved in the turnover of defective long-lived proteins and organelles is crucial for neuronal
homeostasis. We hypothesized that macroautophagic dysregulation in selective brain regions was associated with memory impairment
in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22
young mice and employed immunohistochemistry to assess cellular distribution of proteins involved in the selective degradation
of ubiquitinated proteins via macroautophagy. Values of the discrimination ratio (DR, a measure of short-term recognition
memory performance) in aged mice were significantly lower than those in young mice (median, 0.54 vs. 0.67; p = 0.005, U test). Almost exclusively in aged mice, there were clusters of puncta immunoreactive for microtubule-associated protein 1
light chain 3 (LC3), ubiquitin- and LC3-binding protein p62, and ubiquitin in neuronal processes predominantly in the hippocampal
formation, olfactory bulb/tubercle, and cerebellar cortex. The hippocampal burden of clustered puncta immunoreactive for LC3
and p62 exhibited inverse linear correlations with DR in aged mice (ρ = −0.48 and −0.55, p = 0.044 and 0.018, respectively, Spearman’s rank correlation). These findings suggest that increased accumulation of autophagosomes
within neuronal processes in selective brain regions is characteristic of aging. The dysregulation of macroautophagy can adversely
affect the turnover of aggregate-prone proteins and defective organelles, which may contribute to memory impairment in aged
mice. |
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Keywords: | Autophagy Brain aging MAP1LC3 Object recognition test p62 Ubiquitin |
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