Arsenault D, Julien C, Tremblay C, Calon F.
DHA improves cognition and prevents dysfunction of entorhinal cortex neurons in 3xTg-AD mice.
PLoS One. 2011;6(2):e17397.
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This fairly comprehensive new study from Calon’s group is notable in demonstrating in vivo electrophysiological and biochemical deficits in entorhinal cortex (EC) of LaFerla’s triple Tg mice that can be ameliorated, along with memory deficits, by dietary docosahexanoic acid (DHA). The DHA has no measureable impact on Aβ or tau accumulation. The memory deficits were associated with akinetic episodes and the electrophysiological data that support sub-threshold “seizure-like” activity consistent with biochemical evidence for hyperactivation of glutamate receptors in the EC hippocampal network. The amelioration of these defects with DHA is consistent with possible DHA utility in mild cognitive impairment where functional MRI results suggest hyperactivation of the same network. Electrophysiology further supports an increase in total neuronal membrane surface area in DHA-treated mice. This is consistent with reports in the literature from N. Salem’s group that DHA can increase neuron size in wild-type animals (Ahmad et al., 2002).
These new results encourage an MCI trial for DHA and provide evidence for the hypothesis that DHA can improve neuronal function without altering plaque or tangle pathology. However, while soluble phospho-tau was reduced without altering total Aβ levels in any fraction, it remains unclear whether or not soluble Aβ or tau oligomeric species or a minor intraneuronal species of Aβ or tau might be implicated in the transgene-dependent deficits or in DHA treatment effects.
Ahmad A, Murthy M, Greiner RS, Moriguchi T, Salem N.
A decrease in cell size accompanies a loss of docosahexaenoate in the rat hippocampus.
Nutr Neurosci. 2002 Apr;5(2):103-13.
Yes, this is a very nice, suggestive paper. It is especially interesting that DHA has no effect of amyloid-β and tau levels, yet improved memory performance. Our previous paper reported that this mouse model showed higher levels of pathogenic homocysteic acid (HA) (Hasegawa et al., 2010). HA is known as an agonist of glutamatergic neurons. It is possible that DHA competes with any HA toxic effect on memory.
Recently, we have found that HA is excreted into urine actively in normal humans, but that this is suppressed when Alzheimer's disease begins (submitted). Since HA level in blood increases because of the suppression of urinary excretion of HA, then the increased HA could break through the blood-brain barrier to enter into the brain and damage brain function.
From this paper and our new findings, it could be argued that cognitive impairment in Alzheimer's disease is not caused by amyloid, but by HA.
Hasegawa T, Mikoda N, Kitazawa M, LaFerla FM.
Treatment of Alzheimer's disease with anti-homocysteic acid antibody in 3xTg-AD male mice.
PLoS One. 2010 Jan 20;5(1):e8593.
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