Abstract
Disturbed proteostasis as a particular phenotype of the aging organism has been advanced in C. elegans experiments and is also conceived to underlie neurodegenerative diseases in humans. Here, we investigated whether particular changes in non-disease related proteostasis can be identified in the aged mammalian brain, and whether a particular signature of aberrant proteostasis is related to behavioral performance of learning and memory. Young (adult, n = 30) and aged (2 years, n = 50) Wistar rats were tested in the Morris Water Maze (MWM) to distinguish superior and inferior performers. For both young and old rats, the best and worst performers in the MWM were selected and the insoluble proteome, termed aggregome, was purified from the hippocampus as evidence for aberrant proteostasis. Quantitative proteomics (iTRAQ) was performed. The aged inferior performers were considered as a model for spontaneous, age-associated cognitive impairment. Whereas variability of the insoluble proteome increased with age, absolute changes in the levels of insoluble proteins were small compared to the findings in the whole C. elegans insoluble proteome. However, we identified proteins with aberrant proteostasis in aging. For the cognitively impaired rats, we identified a changed molecular circuitry of proteins selectively involved in F-actin remodeling, synapse building and long-term depression: actin related protein 3 (ARP3), neurabin II (NEB2) and IQ motif and SEC7 domain-containing protein 1 (BRAG2). We demonstrate that aberrant proteostasis is a specific phenotype of brain aging in mammals. We identify a distinct molecular circuitry where changes in proteostasis are characteristic for poor learning and memory performance in the wild type, aged rat. Our findings 1. establish the search for aberrant proteostasis as a successful strategy to identify neuronal dysfunction in deficient cognitive behavior, 2. reveal a previously unknown functional network of proteins (ARP3, NEB2, BRAG2) involved in age-associated cognitive dysfunction.
Highlights
The unraveling of the specific 'pathophysiology' of natural, non disease-associated brain aging is only emerging
We demonstrate an agedependent change in hippocampal proteostasis, indicated by compositional changes in the insoluble proteome, termed aggregome
Wild-type, adult and aged, male Wistar rats were characterized for their cognitive functions in the Morris-WaterMaze (MWM)
Summary
The unraveling of the specific 'pathophysiology' of natural, non disease-associated brain aging is only emerging. Proteomic changes comparing aged and young rodents primarily have been assigned to cellular processes such as glucose metabolism [7,8,9,10,11,12], signal transduction [7,8,9,10,11,13], oxidative stress [9,13], and cytostructure regulation [8,12]. Changes in the expression of proteins that are involved in synaptic processes appear to be more specific to changes in cognition rather than aging [14,15,16,17].
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