When most people think of Alzheimer disease (AD), they imagine parenchymal amyloid plaques. But vascular deposits can be just as damaging. Consider familial dementias caused by the Dutch (E693Q) or Iowa (D694N) mutations in AβPP (see review on Aβ mutations and their physiological effects). Underlying their cognitive and memory defects, these patients have extensive vascular deposits of Aβ, inflammation in and around the vessels, and they are prone to small hemorrhages (see related ARF Live Discussion). One pressing question in the field is how ApoE, the leading risk factor for AD, affects vascular Aβ deposits.
In Sorrento, Bill Van Nostrand from Stony Brook University, New York, addressed this issue when he reported how apolipoprotein E affects amyloid deposits in a mouse model of cerebral amyloid angiopathy (CAA). Previously, he had shown that Tg-SwDI transgenic mice, which express human AβPP harboring Dutch, Iowa, and Swedish (K670N/M671L) mutations, develop early onset deposits of Aβ in both the brain parenchyma and the cerebral vasculature. The parenchymal deposits are diffuse, while deposits in the blood vessels are fibrillar. In-vivo transport studies have shown that these mice have trouble clearing Aβ across the blood-brain barrier (see Davis et al., 2004), though mice with only the Swedish mutation—identical in every other respect to the Tg-SwDI mice—can clear Aβ across the blood-brain barrier, supporting the notion that the Dutch and Iowa mutations somehow affect clearance of Aβ from the brain.
To evaluate what effect ApoE might have on plaque pathology in Tg-SwDI animals, Van Nostrand and colleagues crossed their mice with animals lacking ApoE. The resulting Tg-SwDI/ApoE-negative mice express human AβPP at normal levels, and produce total levels of Aβ1-40 and Aβ1-42 on par with those in Tg-SwDI parents. However, Van Nostrand reported that the microvascular deposition of Aβ, as judged by both immunostaining and thioflavin S reactivity, was almost completely eliminated in animals lacking ApoE, while parenchymal deposits were reduced by about 50 percent. (The only exception was the subiculum, part of the hippocampus, where Aβ deposits increased by about twofold.) The reductions, it turns out, may be due to an effect on Aβ fibrillization. That’s because though the total levels of Aβ are the same in these animals, insoluble Aβ levels were reduced by about 50 percent, and soluble Aβ levels were concomitantly doubled. In fact, an ELISA revealed a 50 percent reduction in oligomeric forms of Aβ in the insoluble fraction. Antibodies developed by Bill Klein at Northwestern University, Chicago (see ARF related news story), which are specific for soluble oligomers, revealed that these species are increased about twofold in the soluble fraction, Van Nostrand reported.
Mice in the ApoE-negative background also had no inflammation surrounding the blood vessels, Van Nostrand reported. Stereological measurements revealed highly significant decreases in the numbers of activated microglia and reactive astrocytes surrounding the microvessels of the cortex and thalamus. This might explain why the animals performed better, Van Nostrand added. On the rotorod test, Tg-SwDI mice do poorly compared to controls (scores are about 50 percent lower), but in the ApoE-/- background their performance was back to normal. (Tg-SwDI mice also exhibit impaired learning and memory in the radial water maze test; ApoE-negative animals are currently being evaluated.)
Work from David Holtzman’s lab, Washington University, St. Louis, has also implicated ApoE in Aβ clearance and deposition in cerebral vessels (see Fryer et al., 2005), and he presented some of that data at Sorrento. Holtzman has found that mouse and human ApoE affect Aβ deposition in the mouse brain very differently. While his data on ApoE-/- mice is in general agreement with results from Van Nostrand’s lab, in mice expressing human ApoE the story is different. Human ApoE delays the onset of Aβ deposition in mice. And when these animals do eventually develop deposits, the ones expressing the ApoE4 isoform get them first, followed by ApoE3, then ApoE2 animals. What’s more, in mice expressing human ApoE4, the burden of the deposits is shifted from the parenchyma to the blood vessels. Holtzman has found that this may be due to an increase in the Aβ40:Aβ42 ratio. The smaller Aβ1-40 peptide has been shown to be more prone to deposition in the vasculature (see ARF related news story), and in mice expressing human ApoE4, levels of Aβ1-40 are higher early in life.
Exactly how mouse ApoE accelerates vascular deposition of Aβ is not well understood. Mouse and human ApoE are obviously not behaving in the same way. Van Nostrand believes that removal of mouse ApoE shifts the Aβ balance in favor of more soluble forms of the peptide. In the absence of adequate clearance mechanisms, these would then accumulate in the brain.
Another way for ApoE to influence brain Aβ would be to alter clearance. It is worth noting that Holtzman has shown that mouse ApoE, in cooperation with ApoJ, aids clearance (see ARF related news story and ApoE symposium). One thing is clear: By figuring out how and why human and mouse ApoE’s differ, much could be learned about Aβ production, deposition, and elimination.—Tom Fagan.
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- Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, Van Nostrand WE. Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J Biol Chem. 2004 May 7;279(19):20296-306. Epub 2004 Feb 25 PubMed.
- Fryer JD, Simmons K, Parsadanian M, Bales KR, Paul SM, Sullivan PM, Holtzman DM. Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci. 2005 Mar 16;25(11):2803-10. PubMed.
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