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The Journal of Neuroscience, December 26, 2007, 27(52):14299-14307; doi:10.1523/JNEUROSCI.3593-07.2007

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Neurobiology of Disease
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

Qiu-Lan Ma,^1,3 Bruce Teter,^1,3 Oliver J. Ubeda,^1,3 Takashi Morihara,^1,3,4 Dilsher Dhoot,^1,3 Michael D. Nyby,¹ Michael L. Tuck,¹ Sally A. Frautschy,^1,2,3 and Greg M. Cole^1,2,3

Departments of ¹Medicine and ²Neurology, University of California, Los Angeles, California 90095, ³Geriatric Research, Education and Clinical Center, Veterans Affairs, Greater Los Angeles Healthcare System, North Hills, California 91343, and ⁴Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine D3, Suita-shi, Osaka 565-0871, Japan

Correspondence should be addressed to Greg M. Cole, Veterans Affairs, Greater Los Angeles Healthcare System Research 151, Building 7, Room A101, 16111 Plummer Street, North Hills, CA 91343. Email: gmcole{at}ucla.edu

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 β-amyloid (Aβ). 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 -3 fatty acid related to reduced AD risk and reduced Aβ 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 Aβ 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.

Key words: SorLA; LR11; Alzheimer; docosahexaenoic acid; diet; omega-3 fatty acid; amyloid

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Received Aug. 8, 2007; revised Oct. 10, 2007; accepted Oct. 30, 2007.

Correspondence should be addressed to Greg M. Cole, Veterans Affairs, Greater Los Angeles Healthcare System Research 151, Building 7, Room A101, 16111 Plummer Street, North Hills, CA 91343. Email: gmcole{at}ucla.edu

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