More than Cholesterol Transporters: Lipoprotein Receptors in CNS Function and Neurodegeneration

Abstract

Members of the low-density lipoprotein (LDL) receptor gene family have a diverse set of biological functions that transcend lipid metabolism. Lipoprotein receptors have broad effects in both the developing and adult brain and participate in synapse development, cargo trafficking, and signal transduction. In addition, several family members play key roles in Alzheimer's disease pathogenesis and neurodegeneration. This review summarizes our current understanding of the role lipoprotein receptors play in CNS function and AD pathology, with a special emphasis on amyloid-independent roles in endocytosis and synaptic dysfunction.

ApoE Receptor 2 Mediation of Trophoblast Dysfunction and Pregnancy Complications Induced by Antiphospholipid Antibodies in Mice

“…In that manner the current findings extend our understanding of the biology of apoER2 beyond its well-established role in CNS development and Alzheimer’s disease (30) and its recently revealed functions in endothelium (26;29). Immunohistochemical analysis of human placenta revealed that apoER2 is abundantly expressed in trophoblasts throughout gestation, and immunoblotting demonstrated that the receptor is also expressed in HTR-8/SVneo and SW.71 cells that retain the characteristics of trophoblasts in culture (33;34;36).…”

“…In another recent study we discovered that apoER2 in endothelium also mediate responses to apolipoprotein E3 that are beneficial to cardiovascular health (29), highlighting the complexities of apoER2 function even in a single cell type. The biology of apoER2 is best understood in neurons in which it is critically involved in central nervous system development and Alzheimer’s disease (30). In the current work, using cell culture and mouse models we tested the hypotheses that apoER2 is expressed in trophoblasts, and that apoER2 mediates trophoblast dysfunction and pregnancy complications induced by aPL.…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Genetic evidence also links lipid metabolism to poor brain outcomes during aging. Thus, the strongest genetic risk factor for late-onset sporadic AD is having an ε4 allele of the gene encoding apolipoprotein E, a protein that transports cholesterol and lipoproteins (Lane-Donovan et al, 2014). Despite considerable investigation, however, the mechanism by which the ε4 APOE isoform endangers neurons is unclear and may not be the result of altered cholesterol metabolism.…”

“…Despite considerable investigation, however, the mechanism by which the ε4 APOE isoform endangers neurons is unclear and may not be the result of altered cholesterol metabolism. Two possibilities are that APOE ε4 lacks the antioxidant (HNE-scavenging) ability of APOE ε2 and ε3 (Pedersen et al, 2000), and that APOE ε4 alters trafficking of proteins (including APP) through the endosomal pathway (Lane-Donovan et al, 2014). …”

Apolipoprotein E polymorphism and functional disability in Brazilian elders: the Bambuí Health and Aging Study

“…Beyond its role in lipid metabolism, apoE is associated with atherosclerosis, neuronal repair and maintenance, inflammation and, possibly, immune response to infectious diseases 1 . Several studies have shown an association between the ε4 allele (rs429358) and age-related diseases such as coronary heart disease 2,3,4 , stroke 5 and Alzheimer's disease 6,7 . The effect of this genotype in mortality has also been widely investigated, but the results are not consistent across all populations 8,9,10,11 .…”