Docosahexaenoic Acid Protects from Dendritic Pathology in an Alzheimer's Disease Mouse Model

Abstract

Learning and memory depend on dendritic spine actin assembly and docosahexaenoic acid (DHA), an essential n-3 (omega-3) polyunsaturated fatty acid (PFA). High DHA consumption is associated with reduced Alzheimer's disease (AD) risk, yet mechanisms and therapeutic potential remain elusive. Here, we report that reduction of dietary n-3 PFA in an AD mouse model resulted in 80%-90% losses of the p85alpha subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin, as in AD brain. The loss of postsynaptic proteins was associated with increased oxidation, without concomitant neuron or presynaptic protein loss. n-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA-restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases where synaptic loss is critical, especially AD.

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

“…DHA depletion aggravated cognitive deficits in the Morris Water Maze in the Tg2576 mouse, while DHA supplementation was protective [7] and reduced amyloid, even late in life [14]. Anti-amyloid activities include modulation of secretase activities via membrane "fluidity"/protein mobility changes or Akt > GSK regulation of ␥-secretase [25] and induction of anti-amyloidogenic transthyretin [26].…”

“…Aged Tg2576 APPsw transgene-positive mice placed from 17 to 22 months on a safflower oil rich, DHA-depleting diet exhibited increased oxidative damage and transgenedependent loss of CNS DHA and massive (70-95%) loss of postsynaptic proteins like the actin-regulatory drebrin, a dendritic spine protein known to be 70-90% lost in AD [7,27] and NR2b [6]. Greater depletion of DHA in Tg2576 may be driven by A␤ aggregates causing DHA oxidation.…”

The role of the drebrin/EB3/Cdk5 pathway in dendritic spine plasticity, implications for Alzheimer’s disease

“…This occurs in mild cognitive impairment (Counts et al, 2012), Alzheimer's disease (Harigaya et al, 1996;Hatanpaa et al, 1999;Shim and Lubec, 2002;Calon et al, 2004;Zhao et al, 2006) and Down's syndrome, where individuals inevitably develop Alzheimer's (Weitzdoerfer et al, 2001;Shim and Lubec, 2002). Whether or not drebrin loss from dendritic spines is causal to cognitive decline in Alzheimer's disease and related cognitive disorders is not fully resolved.…”

“…Transgenic mouse models of familial Alzheimer's disease also show a loss of drebrin from dendritic spines (Lee and Aoki 2012;Calon et al, 2004;Calon et al, 2005;Mahadomrongkul et al, 2005;Aoki et al, 2007;Lacor et al, 2007). Drebrin loss occurs before loss of pre-synaptic markers, such as synaptophysin, suggesting it precedes synapse loss (Counts et al, 2012).…”

“…Although proteolysis at synapses increases in Alzheimer's disease, drebrin breakdown products have not been seen. Proteolytic fragments might have been missed because only one antibody had been used previously to detect drebrin by immunoblotting in Alzheimer's disease brain tissue and transgenic mouse models of Alzheimer's disease and the epitope that it recognises, which is in the C-terminal BB, might be lost from proteolytic fragments (Hatanpaa et al, 1999;Calon et al, 2004;Zhao et al, 2006;Counts et al 2012). It is unclear whether the loss of drebrin through proteolysis causes a loss of drebrin function or a dominant negative effect through one of the proteolytic fragments.…”