Omega-3 fatty acid docosahexaenoic acid increases SorLA/LR11, a sorting protein with reduced expression in sporadic Alzheimer's disease (AD): relevance to AD prevention

J Neurosci. 2007 Dec 26;27(52):14299-307. doi: 10.1523/JNEUROSCI.3593-07.2007.

Abstract

Environmental and genetic factors, notably ApoE4, contribute to the etiology of late-onset Alzheimer's disease (LOAD). Reduced mRNA and protein for an apolipoprotein E (ApoE) receptor family member, SorLA (LR11) has been found in LOAD but not early-onset AD, suggesting that LR11 loss is not secondary to pathology. LR11 is a neuronal sorting protein that reduces amyloid precursor protein (APP) trafficking to secretases that generate beta-amyloid (Abeta). Genetic polymorphisms that reduce LR11 expression are associated with increased AD risk. However these polymorphisms account for only a fraction of cases with LR11 deficits, suggesting involvement of environmental factors. Because lipoprotein receptors are typically lipid-regulated, we postulated that LR11 is regulated by docosahexaenoic acid (DHA), an essential omega-3 fatty acid related to reduced AD risk and reduced Abeta accumulation. In this study, we report that DHA significantly increases LR11 in multiple systems, including primary rat neurons, aged non-Tg mice and an aged DHA-depleted APPsw AD mouse model. DHA also increased LR11 in a human neuronal line. In vivo elevation of LR11 was also observed with dietary fish oil in young rats with insulin resistance, a model for type II diabetes, another AD risk factor. These data argue that DHA induction of LR11 does not require DHA-depleting diets and is not age dependent. Because reduced LR11 is known to increase Abeta production and may be a significant genetic cause of LOAD, our results indicate that DHA increases in SorLA/LR11 levels may play an important role in preventing LOAD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Alzheimer Disease / diet therapy*
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Protein Precursor / genetics
  • Analysis of Variance
  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Docosahexaenoic Acids / administration & dosage*
  • Embryo, Mammalian
  • Female
  • Gene Expression Regulation / drug effects*
  • Humans
  • Male
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Neuroblastoma
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Time Factors

Substances

  • Amyloid beta-Protein Precursor
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Receptors, LDL
  • Sorl1 protein, mouse
  • Docosahexaenoic Acids