Dentate Gyrus Peroxiredoxin 6 Levels Discriminate Aged Unimpaired From Impaired Rats in a Spatial Memory Task

Abstract

Similar to humans, the normal aged rat population is not homogeneous in terms of cognitive function. Two distinct subpopulations of aged Sprague–Dawley rats can be identified on the basis of spatial memory performance in the hole-board paradigm. It was the aim of the study to reveal protein changes relevant to aging and spatial memory performance. Aged impaired (AI) and unimpaired (AU) male rats, 22–24 months old were selected from a large cohort of 160 animals; young animals served as control. Enriched synaptosomal fractions from dentate gyrus from behaviorally characterized old animals were used for isobaric tags labeling based quantitative proteomic analysis. As differences in peroxiredoxin 6 (PRDX6) levels were a pronounced finding, PRDX6 levels were also quantified by immunoblotting. AI showed impaired spatial memory abilities while AU performed comparably to young animals. Our study demonstrates substantial quantitative alteration of proteins involved in energy metabolism, inflammation and synaptic plasticity during aging. Moreover, we identified protein changes specifically coupled to memory performance of aged rats. PRDX6 levels clearly differentiated AI from AU and levels in AU were comparable to those of young animals. In addition, it was observed that stochasticity in protein levels increased with age and discriminate between AI and AU groups. Moreover, there was a significantly higher variability of protein levels in AI. PRDX6 is a member of the PRDX family and well-defined as a cystein-1 PRDX that reduces and detoxifies hydroxyperoxides. It is well-known and documented that the aging brain shows increased active oxygen species but so far no study proposed a potential target with antioxidant activity that would discriminate between impaired and unimpaired memory performers. Current data, representing so far the largest proteomics data set in aging dentate gyrus (DG), provide the first evidence for a probable role of PRDX6 in memory performance.

Lack of the peroxiredoxin 6 gene causes impaired spatial memory and abnormal synaptic plasticity

“…A previous report showed that PRDX6 expression is reduced in aged rats with impaired spatial memory [ 17 ]. In the present study, we found that Prdx6 −/− mice spent less time within the target quadrant in the probe test (Fig.…”

“…It is also related to neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and some diseases caused by chronic inflammatory response [14][15][16]. Gert Lubec et al recently reported the relationship between antioxidant activity of PRDX6 and spatial memory performance [17]. Another study also revealed its role in inhibiting neurogenesis [10].…”

Behavioral and Synaptic Phenotypes of Female Prdx6−/− Mice

“…It is known that PRDX6 may exert either neuroprotective or neurotoxic effects due to its functional diversity and its expression throughout brain subregions [ 14 , 41 ]. A proteomic study revealed that downregulation of PRDX6 in the dentate gyrus (DG) of the hippocampus is associated with spatial memory deficits in aging rats [ 42 ]. Whether the impaired spatial memory of the Prdx6 −/− mice found in this study and previous publications results from a lack of PRDX6 in the DG subregion requires a further gain-of-function study on Prdx6 −/− mice.…”

Responsiveness of dentate neurons generated throughout adult life is associated with resilience to cognitive aging

“…These conclusions have been obtained using the hippocampal‐dependent version of the Morris water maze (measuring reference memory with variable starting points), one of the most widely used behavioral tests to study normal aging in rats; this task does not involve food restriction or the administration of shock to encourage participation of old animals and is very sensitive to the aging process (Kennard & Woodruff‐Pak, 2011; Lubec et al., 2019; Mota et al., 2019). Although inter‐individual differences in memory in aged rats have been demonstrated in other type of mazes (Barrett, Bennie, Trieu, Ping, & Tsafoulis, 2009; Temido‐Ferreira et al., 2018), in object location memory tasks (Lux, Masseck, Herlitze, & Sauvage, 2017), and in the hole‐board task (Lubec et al., 2019), we chose to use the water maze because it is the most widely used task to study the implication of adult‐born neurons in aged rats (our own work, (Bizon & Gallagher, 2003; Marrone, Ramirez‐Amaya, & Barnes, 2012)) whereas their role remains largely unexplored using the other tasks.…”