An international team of researchers
representing several institutions in Japan and the United States has
published promising findings that may stand to benefit people living
with the specter of Alzheimer's and other neurodegenerative diseases, as
well as age-related cognitive decline.
In their paper published in
PNAS, "Leptin in hippocampus
mediates benefits of mild exercise by an antioxidant on neurogenesis and
memory," Yook and colleagues present results from a series of
experiments—murine and in vitro—that elucidate the role of leptin in
cognitive function. Leptin is a hormone that is produced in adipose
tissue and in the hippocampus, the part of the brain where memory and
spatial learning are processed.
The relationship between exercise and improved cognitive function is well established. Likewise, certain
dietary supplements,
for example, docasahexaenoic acid (DHA) have also shown promise in
improving cognition and in slowing or halting cognitive decline. The
effect of both exercise and supplementation with an antioxidant on
plasticity and cognitive function within the hippocampus has until now
been largely unexplored, however. Previous research has demonstrated
that leptin in particular is a promising therapeutic target for
neurodegenerative diseases such as Alzheimer's.
Yook and colleagues sought to answer the particular question of
whether mild exercise (ME) combined with the antioxidant supplement
astaxanthin (AX) might confer benefit in terms of cognitive function and
neuronal plasticity; and whether or not the two interventions—AX and ME
together—could have a synergistic effect beyond the additive effects of
either treatment administered separately. The investigators
"hypothesized that ME-enhanced
hippocampal neurogenesis and memory might be further improved with dietary AX via mediation by a
neurotrophic factor
such as h-LEP [hippocampal leptin]." To test their hypothesis, they
conducted a series of experiments on mice and in vitro using human brain
cell lines.
The first experiment examined the performance of four groups of
wild-type mice on standard tests used to evaluate murine memory and
spatial learning. The mice comprised the following groups: sedentary
with placebo (SE+PL); mild exercise with placebo (ME+PL); sedentary with
astaxanthin (SE+AX); and mild exercise with astaxanthin (ME+AX). The
SE+PL group performed the worst while the ME+PL and SE+AX groups both
performed better. The best performers were the mice in the ME+AX group, a
finding that supports the enhanced effects of both interventions on
memory and spatial learning. The test data were further reinforced by
cell counts of Ki67-positive cells and BrdU/NeuN cells, both measures of
adult hippocampal neurogenesis (AHN), that showed "a strong additional
effect" at work when AX and ME were combined.
To better understand the role of LEP in the changes observed in the
mouse brains, the researchers undertook a DNA microarray and
gene expression analysis,
looking at up- and down-regulated genes in relation to the various
groups of mice, and particularly where the genes overlapped between
treatment groups. Their results, especially with regard to the
antioxidant
ABHD3 gene and the
LEP gene, confirm the synergistic effect of AX and ME on spatial memory and AHN.
Importantly, the study authors also found after further analysis that
circulating plasma leptin levels remained unchanged among treatment
groups, a finding which demonstrates that h-LEP—that is, leptin found in
the hippocampus—is the specific target molecule responsible for the
improvements demonstrated by combined ME+AX therapy. At the protein
level, h-LEP and LEPRa (a leptin receptor), were also correlated with
improvements in spatial memory, while the AKT/STAT3 signaling pathways
were implicated in these improvements as well.
For the in vitro experiment, the investigators used human
neuroblastoma cell lines—cells known to endogenously synthesize
leptin—to observe the effect of exposing them directly to varying
amounts of AX. They noticed a direct dose-dependent response with regard
to expressed leptin, as well as up-regulation in the
ABHD3 and
LEP genes.
Finally, to establish whether or not leptin is required to achieve
the synergistic effect seen with the AX+ME mice, Yook and colleagues
repeated their earlier mouse experiment on
ob/ob knockout mice,
using leptin-deficient animals bred for obesity and diabetes research.
They found that leptin deficiency did indeed play a role, as these mice
performed poorly relative to the wild-type mice, thus confirming leptin
as the crucial component of the AX+ME synergy observed in the prior
experiment.
To further confirm the mediative effect of leptin in the brain, the scientists injected the
ob/ob
mice with leptin over the course of 4 weeks, finding that the
synergistic effects of AX and ME were restored in these mice. The
researchers also observed increased levels of proteins pIGF1R and pP13K
in ME+PL and ME+AX groups, independently of whether or not the
mice were wild-type or knockout.
The researchers offer further discussion of several details of their
study, for example, commenting that "our results of increased leptin and
IGF1R support the possibility that the enhancement of AHN and memory
function by ME+AX may be due to the interplay of both leptin and IGF1R
expression," and also noting a correlation between memory increase and
an increase in levels of the hippocampal receptor LEPRa.
While the results shown here in murine models are certainly
promising, what might this mean in a clinical context for humans? For
one thing, mild exercise for humans has been characterized in this paper
as that which is typical of a yoga or tai chi session, which puts it
within reach of many people. Another factor is the ready availability of
the relatively inexpensive nutritional supplement astaxanthin.
Ultimately, the authors conclude that "our findings advance the
notion that ME combined with a dietary antioxidant such as AX, which
induces endogenous h-LEP, may be an effective nonpharmacological
strategy for preventing or improving cognitive function and brain
health, and for slowing cognitive decline. This strategy may be
particularly useful in vulnerable individuals, including the elderly."
To read more, click
here.
Jul 11 2018
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