Long-Term Dietary Alpha-Linolenic Acid Supplement Alleviates Cognitive Impairment Correlate with Activating Hippocampal CREB Signaling in Natural Aging Rats

Abstract

Alpha-linolenic acid (ALA) is a major precursor of the essential n-3 polyunsaturated fatty acid (PUFA), whose deficiency alters the structure and function of membranes and induces cerebral dysfunctions. The major purpose of this study was to investigate the protective effect of prolonged ALA intake on cognitive function during natural aging. Female Sprague-Dawley rats aged 6 months were chronically treated with ALA and/or lard per day for 12 months. Regular diet-treated rats, both young and old (4 and 18 months old, respectively) served as controls. Rats fed on regular diet during aging showed memory deficits in Morris water maze, which were further exacerbated by lard intake. However, supplementation with ALA for 12 months dose-dependently improved the performance in spatial working memory tasks. Memory performance correlated well with the activation of cAMP response element-binding protein (CREB) and increases in both levels of brain-derived neurotrophic factor (BDNF) and its specific receptor tyrosine kinase B (TrkB) phosphorylation in the hippocampus. Further study identified that hippocampal extracellular signal-related kinase (ERK) and Akt rather than calcium calmodulin kinase IV (CaMKIV) and protein kinase A (PKA), the upstream signalings of CREB, were also activated by ALA supplement. Moreover, memory improvement was accompanied with alterations of hippocampal synaptic structure and number, suggestive of enhancement in synaptic plasticity. Together, these results suggest that long-term dietary intake of ALA enhances CREB/BDNF/TrkB pathway through the activation of ERK and Akt signalings in hippocampus, which contributes to its ameliorative effects on cognitive deficits in natural aging.

Melatonin alleviates cognition impairment by antagonizing brain insulin resistance in aged rats fed a high‐fat diet

“…CREB activity and BDNF levels are associated with neurodegenerative diseases, because they play essential roles in acquisition learning and retention memory, as well as in activity‐dependent synaptic plasticity . In accordance with previous reports, the reduced hippocampal CREB activity and BDNF levels observed by us in HFD‐fed, aged rats coincided with impairments of spatial cognitive ability and synaptic plasticity. Importantly, MLT supplementation restored hippocampal CREB activity and BDNF levels.…”

“…MWM tests were performed between 9:00 and 17:00, and conducted as described previously . Briefly, animals were pretrained (no platform) for 2 days to acclimatize to the water maze pool (diameter 150 cm, depth 50 cm, temperature 22 ± 1°C).…”

CDKL5 deficiency predisposes neurons to cell death through the deregulation of SMAD3 signaling

“…We additionally found that CDKL5‐dependent phosphorylation of SMAD3 does not directly affect SMAD3 activity, but that CDKL5 deficiency causes a reduction in SMAD3 protein levels and, consequently, in activity in Cdkl5 KO neurons. Phosphorylation at different sites of SMAD3 contributes to its stability . Most SMAD proteins can be polyubiquitinated and degraded in either a ligand‐dependent or a ligand‐independent manner .…”

Protective effects of macamides fromLepidium meyeniiWalp. against corticosterone-induced neurotoxicity in PC12 cells

“…63 Long-term dietary intake of ALA activates Akt signaling in the hippocampus of natural aging rats. 64 CREB is a transcription factor involved in critical functions such as neuronal plasticity and survival. CREB is phosphorylated at Ser133, and p-CREB is its active form.…”