The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease

Abstract

Alzheimer's disease (AD) is the most common cause of dementia in the elderly population, currently affecting 46 million people worldwide. Histopathologically, the disease is characterized by the occurrence of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles containing the microtubule-associated protein tau. Aβ peptides are derived from the sequential processing of the amyloid precursor protein (APP) by enzymes called secretases, which are strongly influenced by the lipid environment. Several vitamins have been reported to be reduced in the plasma/serum of AD-affected individuals indicating they have an impact on AD pathogenesis. In this review we focus on vitamin E and the other lipophilic vitamins A, D, and K, and summarize the current knowledge about their status in AD patients, their impact on cognitive functions and AD risk, as well as their influence on the molecular mechanisms of AD. The vitamins might affect the generation and clearance of Aβ both by direct effects and indirectly by altering the cellular lipid homeostasis. Additionally, vitamins A, D, E, and K are reported to influence further mechanisms discussed to be involved in AD pathogenesis, e.g., Aβ-aggregation, Aβ-induced neurotoxicity, oxidative stress, and inflammatory processes, as summarized in this article.

Keywords: Alzheimer´s disease; lipids; tocopherol; tocotrienol; vitamin A; vitamin D; vitamin E; vitamin K.

Figure 1

Proteolytic processing of the amyloid precursor protein (APP) and its modulation by vitamins A, D, E, and K. APP can be cleaved in two different processing pathways. In the amyloidogenic processing pathway (right) APP is first cleaved by β-secretase BACE1 (β-site APP cleaving enzyme 1) generating soluble sAPPβ (soluble β-secreted APP) and the C-terminal anchored fragment C99/βCTF (β-cleaved C-terminal fragment), which is further cleaved by the γ-secretase complex to release amyloid-β (Aβ) peptides. Aβ peptides can be degraded by several processes or aggregate to build up neurotoxic amyloid plaques. In the non-amyloidogenic pathway (left) APP is first cleaved within the Aβ domain by α-secretases (members of the ADAM (a disintegrin and metalloprotease) protein family) leading to the release of soluble sAPPα (soluble α-secreted APP) and the generation of the C-terminal membrane-tethered fragment C83/α-CTF (α-cleaved C-terminal fragment), which is also cleaved by the γ-secretase complex to release the non-toxic peptide p3. In both processing pathways the APP intracellular domain (AICD) is liberated into the cytosol. GE = gene expression; S = sorting; A = activity; RA = retinoic acid; Vit = vitamin; TP = tocopherol; PL = protein level; TT = tocotrienol; PS1 = presenilin 1; PS2 = presenilin 2; IDE = insulin degrading enzyme; NEP = neprilysin. The effects of vitamins on AD-relevant mechanisms are indicated by solid arrows, the impact of vitamins on lipid homeostasis is delineated by dashed arrows. + = increase; − = decrease.