M. D. Neely, T. J. Montine

Department of Pathology and the Centers for Molecular Neuroscience and Molecular Toxicology, Vanderbilt University Medical School, MCN U4216, 21st Avenue South, Nashville, Tennessee 37232-2561, USA. Correspondence: M. Diana Neely, Vanderbilt University Medical School, Department of Pathology, Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2561, USA. Tel. 615 322 3699. Fax. 615 343 9825. E-mail: diana.neely@mcmail.vanderbilt.edu

Abstract: Alterations in lipid homeostasis have been suggested to play a role in the pathogenesis of Alzheimer's disease (AD). This hypothesis is supported by the observed changes in lipid content and composition of AD brains when compared to age-matched control brains. The association between the e4 allele of the apolipoprotein E gene and increased risk of AD implicates lipoproteins in the pathogenesis. Lipoproteins are macromolecular particles responsible for lipid trafficking and metabolism. CNS lipoproteins are different from their plasma counter parts. We review the current understanding of the structure and functions of CNS lipoproteins. In addition to mediating lipid trafficking and metabolism, there is increasing evidence that apoE-containing lipoproteins are also involved in dendritic remodeling and synaptogensis and maintenance of the synapto-dendritic complexity during aging. Interestingly, these functions have been shown to be apoE-isoform specific with apoE4 lacking the activities of apoE3 and apoE2. In addition to the association between apoE4 and an increased risk of AD, oxidative stress is believed to play a role in the pathogenesis of this disease. Indeed evidence of lipid peroxidation in cerebral spinal fluid (CSF) lipoproteins from AD patients has been observed. Oxidation of lipoproteins not only eliminates their supportive roles in neurite outgrowth and synaptogenesis, but actually transforms them into neurotoxic agents. The elucidation of the pathways and mechanisms by which apoE-isoform and oxidation affect lipoprotein function in the CNS remains a challenge for scientist in the field of neurodegenerative disease.

Abbreviations: AD, Alzheimer's disease; apo, apolipoprotein; CSF, cerebral spinal fluid; HDL, high-density lipoproteins; LDL, low density lipoproteins; VLDL, very low density lipoprotein; ROS, reactive oxygen species.