The Impact of Cholesterol, DHA, and Sphingolipids on Alzheimer’s Disease

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 [73–79].

(a) Effect of DHA

Affected pathway	Mechanism of action
Nonamyloidogenic processing	sAPPα ↑
	ADAM 17 protein stability ↑
Amyloidogenic processing	Aβ ↓
	β-Secretase activity ↓
	Endosomal BACE1 ↓
	γ-Secretase activity ↓
	PS1 shift: raft → non-raft
Aβ Oligomerization and toxicity	Aβ Fibrillation ↓
	Soluble toxic oligomers ↓
	Aβ Phagocytosis ↑
Cholesterol homeostasis	HMG-CoA reductase activity ↓
	Cholesterol de novo synthesis ↓
	Cholesterol shift: raft → non-raft
Other non-APP-mediated pathways/mechanisms	SorLA/R11 ↑, a sorting protein reduced in AD
	Neuronal differentiation ↑
	Protection against synaptic loss, Synaptogenesis ↑
	Neurogenesis ↑
	Inflammation ↓
	Reactive oxidative species ↓

(b) Effect of DHA derivates

Affected pathway		Mechanism of action
NPD1	Nonamyloidogenic processing	sAPPα ↑
		ADAM 10 maturation ↑
	Amyloidogenic processing	Aβ ↓
		sAPPβ ↓
		BACE 1 protein level ↓
	Aβ Toxicity	Neuroprotective and antiapoptotic
		Soluble toxic oligomers ↓