Brain lipid metabolism, apolipoprotein E and the pathophysiology of Alzheimer's disease.
Brain lipid homoeostasis is critical during neurodevelopment, repair after traumatic brain injury and for the maintenance of efficient neurotransmission. Several neurodegenerative disorders occur as a direct result of neuronal lipid dysfunction and underlying disease processes that are associated with Alzheimer's disease (AD) also appear to be related to an imbalance in brain lipid homeostasis. In support of this latter hypothesis, recent genome wide association studies have confirmed and extended the now widely reproduced association between the epsilon4 allele of the apolipoprotein E gene (APOE) and late onset AD. Even in populations with low APOE epsilon4 allele frequency, gene dosage of APOE epsilon4 increases the age-adjusted relative risk for developing the more common late onset form of AD. A major role for apolipoprotein E (apoE) in the brain is to maintain a constant supply of neuronal lipids for rapid and dynamic membrane synthesis thus ensuring efficient neurotransmitter release and the propagation of action potentials. Additionally, apoE synthesized primarily by glia is critical for the elimination of toxic brain-derived Abeta peptides. In addition to apoE isoform, the overall levels of apoE appear to be important determinants for brain Abeta clearance. Susceptibility to AD in APOE epsilon4 carriers may occur early since brain activity and the accumulation of Abeta in brain parenchyma both appear well in advance of disease onset. Given the pivotal role apoE plays in maintaining neuronal membrane homeostasis, elevating the levels of apoE in brain may be a viable therapeutic strategy for the prevention and/or treatment of AD.
Bales
Kelly R
KR
Neuroscience Research Unit, Pfizer Global Research & Development, Groton, CT 06430, USA. Kelly.Bales@Pfizer.com
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D053327:Apolipoprotein E4 / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*
D053327:Apolipoprotein E4; D001057:Apolipoproteins E