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Title: Walnut diet reduces accumulation of polyubiquitinated proteins and inflammation in the brain of aged rats

Author
item Poulose, Shibu
item BIELINSKI, DONNA F. - Tufts University
item Shukitt-Hale, Barbara

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/8/2012
Publication Date: 8/20/2012
Citation: Poulose, S., Bielinski, D., Shukitt Hale, B. 2012. Walnut diet reduces accumulation of polyubiquitinated proteins and inflammation in the brain of aged rats. Journal of Nutritional Biochemistry. DOI: 10.1016/j.jnutbio.2012.06.09.

Interpretive Summary: Many age-related neurodegenerative diseases are marked by a buildup of misfolded proteins in the brain. The accumulation of these potentially toxic proteins in brain increases with age, in part due to increased inflammation and oxidative stress. Walnuts, rich in omega fatty acids, have been shown to improve memory, cognition and neuronal effects related to oxidative stress and inflammation in animals and human trials. The current study found that feeding 19-month-old rats with a 6% or 9% walnut diet significantly reduced the aggregation of these proteins and activated autophagy, a neuronal housekeeping function, in two regions of the brain associated with memory and cognition. The results suggest that a walnut-supplemented diet may provide neuroprotection by activating the autophagy process in the brain, in addition to antioxidant and anti-inflammatory benefits.

Technical Abstract: An increase in the aggregation of misfolded/damaged polyubiquitinated proteins has been the hallmark of many age-related neurodegenerative diseases. The accumulation of these potentially toxic proteins in brain increases with age, in part due to increased oxidative and inflammatory stresses. Walnuts, rich in omega fatty acids, have been shown to improve memory, cognition and neuronal effects related to oxidative stress (OS) and inflammation (INF) in animals and human trials. The current study found that feeding 19-month-old rats with a 6% or 9% walnut diet significantly reduced the aggregation of polyubiquitinated proteins and activated autophagy, a neuronal housekeeping function, in the striatum and hippocampus. Walnut-fed animals exhibited up-regulation of autophagy through inhibiting phosphorylation of mTOR, up-regulating ATG5 and Beclin 1 (both ubiquitin-binding proteins), and increasing conversion of MAP1BLC3-I to LC3-II. The clearance of polyubiquitinated protein aggregates such as p62/SQSTM1 was more profound in hippocampus, a critical region in the brain involved in memory and cognitive performance, than striatum. The clearance of ubiquitinated aggregates was in tandem with significant reductions in OS/INF, as indicated by the levels of P38-MAP kinase and phosphorylations of NF-KB and CREB. The results demonstrate the effectiveness of a walnut-supplemented diet in activating the autophagy function in brain beyond its traditionally known antioxidant and anti-inflammatory benefits.