Abstract
Reduced brain levels of docosahexaenoic acid (C22:6n-3), a neurotrophic and neuroprotective fatty acid, may contribute to cognitive decline in Alzheimer's disease. Here, we investigated whether the liver enzyme system that provides docosahexaenoic acid to the brain is dysfunctional in this disease. Docosahexaenoic acid levels were reduced in temporal cortex, mid-frontal cortex and cerebellum of subjects with Alzheimer's disease, compared to control subjects (P = 0.007). Mini Mental State Examination (MMSE) scores positively correlated with docosahexaenoic/α-linolenic ratios in temporal cortex (P = 0.005) and mid-frontal cortex (P = 0.018), but not cerebellum. Similarly, liver docosahexaenoic acid content was lower in Alzheimer's disease patients than control subjects (P = 0.011). Liver docosahexaenoic/α-linolenic ratios correlated positively with MMSE scores (r = 0.78; P<0.0001), and negatively with global deterioration scale grades (P = 0.013). Docosahexaenoic acid precursors, including tetracosahexaenoic acid (C24:6n-3), were elevated in liver of Alzheimer's disease patients (P = 0.041), whereas expression of peroxisomal d-bifunctional protein, which catalyzes the conversion of tetracosahexaenoic acid into docosahexaenoic acid, was reduced (P = 0.048). Other genes involved in docosahexaenoic acid metabolism were not affected. The results indicate that a deficit in d-bifunctional protein activity impairs docosahexaenoic acid biosynthesis in liver of Alzheimer's disease patients, lessening the flux of this neuroprotective fatty acid to the brain.
Highlights
Alzheimer’s disease is a neurodegenerative disorder characterized clinically by progressive cognitive impairment [1]
Docosahexaenoic acid levels in brain Brain levels of non-esterified (‘free’) docosahexaenoic acid were measured in extracts of temporal cortex, mid-frontal cortex and cerebellum from a total of 17 control subjects and 37 Alzheimer’s disease patients
Our findings provide new evidence in support of such association and further reveal the existence of a positive correlation between brain docosahexaenoic acid levels and cognitive status
Summary
Alzheimer’s disease is a neurodegenerative disorder characterized clinically by progressive cognitive impairment [1]. How aging interacts with other risk factors for Alzheimer’s disease [3] is still unknown. It appears, that certain age-related pathologies that are closely associated with systemic dysfunctions in lipid metabolism – including obesity and diabetes – might be involved [1]. Mammals obtain docosahexaenoic acid directly from dietary sources, especially fish, but can produce it in liver from n-3 fatty acid precursors present in plants [9,10,11]. When the diet does not provide an adequate supply of these foods, as is often the case in contemporary populations [12], the liver’s capacity to generate docosahexaenoic acid may become critical to keep normal the brain levels of this fatty acid [9,11,13,14]
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