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- W2616369314 abstract "Epidemiological studies implicated n-3 fatty acid DHA as protective for AD. DHA and the n-6 linoleic acid (LA) alter pathogenesis in APP Tg2576 mice; high n-6 LA exacerbated the AD phenotype while DHA supplementation limited excitatory postsynaptic marker loss and reduced amyloid accumulation, apparently by reducing Aβ production. GSK3β has been implicated in Aβ toxicity in vitro and induction of tau pathology and may be DHA sensitive. To explore GSK3β's role in Aβ oligomer activity in vivo, the fatty acid effect on amyloid and test GSK3β inhibition by DHA. Oligomer and GSK3β inhibitor effects were tested in i.c.v. infused rats and dietary LA/ DHA were tested in aged wild-type and APP Tg2576 mice. We find that high LA markedly exacerbates APP transgene-dependent defects in neurotrophic signal transduction involved in synaptic plasticity (PI3-K/Akt/ GSK3β, Erk/ CREB and PAK pathways). DHA protected against some, but not all defects. In aging APP Tg mice, DHA increased inhibitory phosphorylation of the major tau kinase, GSK3β. This is predicted to limit Aβ oligomer-induced cognitive deficits and tau pathology. GSK3β inhibition blocked Aβ oligomer-induced JNK and cognitive deficits in oligomer-infused rats. DHA reduced Aβ accumulation in APP Tg mice by a novel mechanism involving APP sorting. APP Tg mice on the high n-6 diet have highly significant loss of the actin-regulatory dendritic spine protein, drebrin. We argue that oligomer-induced drebrin-related defects play a critical role in initiating cognitive deficits. AD clinical trial results found that DHA (as fish oil) had little impact on cognitive decline in established AD patients, but might have been effective at the earliest stages (MMSE >27). Major region-specific drebrin loss has been reported to begin in MCI with a sharp fall-off at very early stages of AD (MMSE>26) -without further progression. DHA can limit Aβ production in vivo by a novel mechanism. Oligomer-induced dendritic spine loss is reflected in drebrin loss and should be a major target. Because it occurs very early, treatments that may mitigate oligomer-induced postsynaptic pathology, including DHA intervention, should begin very early, either in MCI or with primary prevention." @default.
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- W2616369314 date "2007-07-01" @default.
- W2616369314 modified "2023-09-27" @default.
- W2616369314 title "O1-02-08: DHA, amyloid, GSK3β, trophic signaling and AD prevention" @default.
- W2616369314 doi "https://doi.org/10.1016/j.jalz.2007.04.094" @default.
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