Apolipoprotein E Linked to Alzheimer's Disease Plaque Formation

It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen. In the nervous system, nonneuronal cell types, most notably astroglia and microglia, are the primary producers of ApoE, while neurons preferentially express the receptors for ApoE. There are seven currently identified mammalian receptors for ApoE, which belong to the evolutionarily conserved low-density lipoprotein receptor gene family. ApoE is polymorphic with three major isoforms, ApoE2, ApoE3, and ApoE4. E2 is associated with the genetic disorder hyperlipoproteinemia type III and with both increased and decreased risk for atherosclerosis. E3, the "neutral" form, is found in approximately 64% of the population. E4 has been implicated in atherosclerosis and Alzheimer's disease, impaired cognitive function, and reduced neurite outgrowth.

Investigators at Washington University School of Medicine (St. Louis, MO, USA) hypothesized that LDLR overexpression in the brain would decrease ApoE levels, enhance amyloid beta clearance, and decrease amyloid beta-plaque deposition. To test this hypothesis, they created several transgenic mice that overexpressed LDLR in the brain.

Results published in the December 10, 2009, issue of the journal Neuron revealed that ApoE levels in these mice decreased by 50%-90% relative to wild type mice. Furthermore, LDLR overexpression dramatically reduced amyloid beta aggregation and enhanced amyloid beta clearance from the brain extracellular space. Plaque-associated inflammatory responses were attenuated in LDLR transgenic mice.

"This suggests the intriguing possibility that some of the compounds and strategies now in development to treat heart disease, many of which boost LDLR levels to lower blood cholesterol, may one day be modified and adapted for use in Alzheimer's disease," said senior author Dr. David M. Holtzman, professor of neurology at Washington University School of Medicine.

"We think that LDLR's ability to lower amyloid beta is a result of its effects on ApoE levels, but we have not proven that yet," said Dr. Holtzman. "ApoE binds to amyloid beta, so one possibility is that ApoE and amyloid beta in a combined form are both being cleared from the brain when they bind to LDLR."

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Washington University School of Medicine