Table 1: Summary of mechanisms of DHA and DHA derivates on APP processing. DHA both affects amyloidogenic and non-amyloidogenic pathways via multiple mechanisms resulting in a decrease in Aβ production. In opposite to cholesterol it has been reported that DHA decreases Aβ aggregation and toxicity. Direct effects of DHA on APP processing are further enhanced by a DHA-mediated decrease in cholesterol de novo synthesis [7379].
(a) Effect of DHA

Affected pathwayMechanism of action

Nonamyloidogenic processingsAPPα
ADAM 17 protein stability ↑

Amyloidogenic processingAβ
β-Secretase activity
Endosomal BACE1
γ-Secretase activity
PS1 shift: raft → non-raft

Aβ Oligomerization and toxicityAβ Fibrillation
Soluble toxic oligomers ↓
Aβ Phagocytosis ↑

Cholesterol homeostasisHMG-CoA reductase activity
Cholesterol de novo synthesis
Cholesterol shift: raft → non-raft

Other non-APP-mediated pathways/mechanismsSorLA/R11 ↑, a sorting protein reduced in AD
Neuronal differentiation ↑
Protection against synaptic loss, Synaptogenesis ↑
Neurogenesis ↑
Reactive oxidative species

(b) Effect of DHA derivates

Affected pathwayMechanism of action

NPD1Nonamyloidogenic processingsAPPα
ADAM 10 maturation ↑
Amyloidogenic processingAβ
BACE 1 protein level
Aβ ToxicityNeuroprotective and antiapoptotic
Soluble toxic oligomers