Although AD is conceptualized as a neurodegenerative disease of the brain, there is increasing awareness that it may involve abnormalities in multiple peripheral tissues34, 77, 78,79–83
. In this regard, several reports indicate that the liver may play an important role in peripheral Aβ clearance from the central nervous system84–86
. To identify potential mechanisms responsible for the observed DHA deficit in AD brain, we focused our attention on the liver because of the essential contribution of this organ in supplying DHA to the brain1
(). Our analyses showed that liver tissue from AD patients contains reduced levels of DHA, but elevated levels of shorter chain omega-3 fatty acids precursors – from α-linolenic to tetracosahexaenoic acid (24:6 omega-3). This profile cannot be caused by a nutritional deficit in omega-3 fatty acids. Rather, the profile suggests a defect in the last step of DHA biosynthesis – the β-oxidative conversion of tetracosahexaenoic acid into DHA, which is catalyzed by DBP in liver peroxisomes. Two additional findings support this interpretation. First, expression of the hydroxysteroid (17-β) dehydrogenase 4 (HSD17B4
) gene, which encodes for DBP58, 59, 87
, is lower in AD. Second, pristanic acid and phytanic acid, two substrates for liver DBP activity, accumulate in the liver of AD patients. Notably, no other gene included in our panel was significantly altered in liver tissue from AD patients, including those encoding for proteins involved in peroxisome biogenesis, such as PEX13, PEX14
. These results are consistent with those of previous studies, which have shown that genetic mutations that selectively disrupt DBP activity reduce DHA levels in human plasma and brain88, 89
. The pathological changes that trigger the down-regulation of liver DBP expression in AD are still unknown. One possible candidate is oxidative stress, which is known to accelerate age-dependent damage to peroxisomes90, 91
. Additional studies should also evaluate the existence of other possible links between liver peroxisomal function and cognition. Moreover, other aspects of DHA metabolism – such as transport and ApoE genotype14, 92–94
– might contribute to the observed changes and await further investigation.
Figure 3 Overview of DHA biosynthesis in liver. Liver transforms diet-derived α-linolenic acid (18:3 omega-3) into DHA (22:6 omega-3). In the endoplasmatic reticulum, the serial activities of Δ6 and Δ5 desaturases (encoded by the FADS2 (more ...)
Importantly, the functional significance of the peroxysomal liver dysfunction is underscored by the identification of a strong positive correlation between liver DHA content and cognitive status, indicating a previously unrecognized association between hepatic DHA homeostasis and global cognition1
. Although it is well established that patients with advanced liver diseases (e.g., hepatitis C, non-alcoholic liver steatosis and end-stage liver disease) show a decline in cognitive abilities (e.g.
, hepatic encephalophaty)95–97
, our novel findings reveal that, even in the absence of overt liver pathology, subtle molecular dysfunctions in the liver can be associated with dementia and AD pathology.
It appears, however, that an overall healthy liver is required for optimal DHA biosynthesis. It has been reported that during conditions of hepatic stress such as in chronic alcohol intake98, 99
, and liver steatosis and injury100, 101
, the levels of hepatic DHA are compromised. Supplementation of DHA has been suggested as a new therapeutic approach in the treatment of these conditions102, 103
. Further research will be required to determine the contribution of a dysfunctional hepatic DHA biosynthesis to cognition in relation to liver injury or impaired functioning.