Docosahexaenoic Acid Reduces Amyloid β Production via Multiple Pleiotropic Mechanisms

Abstract

Alzheimer disease is characterized by accumulation of the ␤-amyloid peptide (A␤) generated by ␤-and ␥-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing ␤-and ␥-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of ␣-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in ␥-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing A␤ release. DHA has a typical pleiotropic effect; DHA-mediated A␤ reduction is not the consequence of a single major mechanism but is the result of combined multiple effects.

Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

“…Little is known about the incorporation of DHA-derived epoxides or diols into phospholipids, but this is highly likely given that the epoxides of arachidonic acid (the EETs) can be esterified to phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositols (Capdevila et al, 2000). This is not the first time a link between DHA and the -secretase has been reported, and although DHA increased -secretase activity in vascular smooth muscle cells (Delbosc et al, 2008), it was found to redistribute cholesterol out of lipid rafts Stillwell, 2008, 2009), thereby decreasing -secretase activity in a neuroblastoma cell line (Grimm et al, 2011 Adenovirus generation and Müller cell transduction. The human sEH (Ephx2) cDNA sequence, with a C-terminal Myc/His tag, was excised via NotI-PmeI from pcDNA3.1myc/His as previously described (BarbosaSicard et al, 2009) and cloned into the NotI-EoRV site of the cloning plasmid pAdTrackCMV.…”

“…19,20-DHDP is of particular interest, given that it was the most abundant lipid detected in the retinal lipid profile and that its precursor DPA has previously been reported to modulate the activity of the -secretase (Delbosc et al, 2008;Grimm et al, 2011). When activated, the -secretase cleaves the Notch intracellular domain (NICD), which then either undergoes rapid proteasome degradation or translocates to the nucleus and binds to transcription factors (Boulton et al, 2008).…”

[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐11C]‐DHA

“…From plasma samples collected at 0, 3,7,10,15,20,40, and 60 minutes after infusion of [1-11 C]-DHA, total lipids were extracted into chloroform:methanol (1:1) as previously described [24].…”

Metabolismo, oxidação e implicações biológicas do ácido docosahexaenoico em doenças neurodegenerativas

“…A combinação dos efeitos tóxicos de ambos, os agregados iniciais oligoméricos e o depósito de placas Aβ insolúveis, leva a um rompimento neuronal e a uma morte celular eventual, que por sua vez é responsável pelo declínio cognitivo irreversível encontrado na AD. 89,90 A riqueza dos dados coletados a partir de ensaios in vitro, em cultura celular e modelos de animais transgênicos para AD suporta uma associação direta de PUFAs ômega-3, principalmente DHA, com o processamento amiloide no cérebro. PUFAs ômega-3 como componentes integrais de membrana podem agir para alterar o processamento amiloidogênico de várias maneiras distintas incluindo: a) facilitar a interação de α-secretase com APP para produzir fragmentos não tóxicos e evitar a formação de Aβ; b) proteger a sequência de reconhecimento e sítio de clivagem intramembrana essencial para γ-secretase; c) servir como um local dissipador para os radicais livres que reduzem o aumento da atividade enzimática γ-secretase, que pode ser induzida por danos causados pelos radicais livres para o complexo de proteínas, o que é importante para a regulação da função normal γ-secretase e, d) inibir diretamente a fibrilação e formação de espécies oligoméricas de Aβ.…”

“…Esses dados indicam que o DHA pode ter um efeito mais eficaz para prevenção do que para o tratamento dessa doença. 90 Estudos com cultura celular demonstraram consistentemente uma redução de 20% da produção de Aβ depois do tratamento com o DHA. 89,93,94 As atividades de ambas β-e γ-secretase estavam diminuídas quando essas culturas celulares foram tratadas com DHA, o que está de acordo com os níveis reduzidos de Aβ.…”