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.
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.
Ma
Qiu-Lan
QL
Department of Medicine, University of California, Los Angeles, California 90095, USA.
Teter
Bruce
B
Ubeda
Oliver J
OJ
Morihara
Takashi
T
Dhoot
Dilsher
D
Nyby
Michael D
MD
Tuck
Michael L
ML
Frautschy
Sally A
SA
Cole
Greg M
GM
D000367:Age Factors; D000544:Alzheimer Disease / Q000178:diet therapy* / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000008:administration & dosage*; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009447:Neuroblastoma; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; C491168:Sorl1 protein, mouse; D004281:Docosahexaenoic Acids