Apolipoprotein E

In contrast to clusterin, levels of apoE have been reported to be reduced in the frontal cortex and hippocampus in AD, with the reduction variously reported as proportional to the apoE4 allele dose9 or independent of apoE type.16 The mRNA for apoE, on the other hand, has been reported to be significantly more abundant in AD than control brain tissue,17,18 with the amount in AD being decreased in relation to the apoE4 gene dose.17 The upregulation of the mRNA occurs in reactive astrocytes.18 And, astrocytes rich in the apoE gene appear to shift in AD hippocampus from the neuropil to regions with densely packed

neurons.

The discrepancies between reports on the levels of the protein and its mRNA may depend upon the cases or regions of brain used, but need to be clarified by further work. Another possibility is that some of the apoE in AD brain is so tightly bound to amyloid that it does not appear as apoE in the separation of brain extracts. It has already been reported that, in attempts to purify amyloid, a complex of apoE (or apoE fragments) and amyloid purifies as such from AD brain.20,21 Complexes of apoE with soluble Ap peptides have been found in AD brain supernatants.22

Reports of immunohistochemical studies on AD brain with antibodies to apoE emphasize the staining of plaques and NFTs, but differ somewhat in the extent of such staining. The senile plaques found in aged, nondemented individuals are also variably

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Fig. 7.1. Clusterin immunostaining in the entorhinal cortex in Alzheimer's disease (A) and the Parkinson dementia complex of Guam (B). (A) The antibody against clusterin stained many dystrophic neurites, NFTs and amyloid plaques in Alzheimer's disease. (B) In the Parkinson's dementia complex, dystrophic neurites and some NFTs are intensely immunore-active, while most NFTs remain unstained. Both photomicrographs are at the same magnification; bar in (B) = 100 ^m.

immunopositive for apoE.23 Astrocytes,24,25 blood vessels and some neurons are also stained as they are in normal brain.24,26,27 Similar staining of neurons and glial cells for apoE has been found in transgenic mice bearing a human apoE gene, and this pattern differs from the staining seen in wild type mice.28

With regard to the senile plaques, most reports suggest that apoE antibodies label most but not all classic senile plaques (Fig. 7.2) and some diffuse amyloid deposits.29,30 All plaques in the hippocampus, and especially in CA1, have been found positive for apoE, while some in cortical regions were not.31 Ap plaques showing high apoE immunoreactivity have been reported to be localized in layers II, III and V of the neocortex, with those in layer I being generally unlabeled.32 Yamaguchi et al33 reported that senile plaques were consistently labeled with the apoE antiserum even in early stages of plaque formation. In double staining experiments on temporal cortical samples from AD patients, apoE was present in 83-86% of neuritic plaques but in only about 6% of non-neuritic plaques whether they were of the diffuse or "burned out" type.25 In the neocortex in general, apoE-positive plaques were greater

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Fig. 7.2. Comparison of apoE (A, C) and Aß (B, D) demonstrated with the E50 antibody against Aß17-31, immunoreactivity in the CA1 region of the hippocampus in nearby sections of a case of Alzheimer's disease (A, B) and a case of the Parkinson's dementia complex of Guam (C, D). (A) The apoE antibody in AD showed intense staining of some senile plaques with lighter staining of tangles. (B) With the antibody to Aß, plaques in AD tissue are intensely stained but the tangles are not reactive. (C) Many extracellular NFTs are positive with the antibody to apoE in the case of Parkinson's dementia of Guam (PDC). (D) Only a few of the NFTs in the PDC case show immunoreactivity with the antibody to Aß. No plaques or diffuse deposits are visible in this field. All photomicrographs are at the same magnification; bar in (D) = 200 |im.

Fig. 7.2. Comparison of apoE (A, C) and Aß (B, D) demonstrated with the E50 antibody against Aß17-31, immunoreactivity in the CA1 region of the hippocampus in nearby sections of a case of Alzheimer's disease (A, B) and a case of the Parkinson's dementia complex of Guam (C, D). (A) The apoE antibody in AD showed intense staining of some senile plaques with lighter staining of tangles. (B) With the antibody to Aß, plaques in AD tissue are intensely stained but the tangles are not reactive. (C) Many extracellular NFTs are positive with the antibody to apoE in the case of Parkinson's dementia of Guam (PDC). (D) Only a few of the NFTs in the PDC case show immunoreactivity with the antibody to Aß. No plaques or diffuse deposits are visible in this field. All photomicrographs are at the same magnification; bar in (D) = 200 |im.

in E4/4 AD cases than in those with other genotypes but, overall, were less numerous than Aß-positive plaques.35

Apolpoprotein E immunoreactivity was found in association with senile plaques in all brain regions examined but there was marked regional variation in its occurrence in diffuse deposits. Staining has been reported as absent27 or strong in many cerebellar (cf. refs. 11,33,34) diffuse plaques but was absent or weak in such deposits in the striatum and thalamus. (cf. refs. 34,35) It is speculated that the difference is due to the reported presence of small amounts of fibrillar amyloid in the diffuse deposits in the cortex and cerebellum.36 The labeling of diffuse deposits for apoE was more common than for clusterin in the cortex of AD (and Down's syndrome) cases.11

Using confocal laser scan microscopy, Nishiyama et al37 found a clear difference in the distribution and shape of deposits stained with antibodies to apoE and Aß. Several Aß deposits of typical and primitive plaques were often included in one diffuse deposit of apoE. Some apoE deposits did not exhibit any Aß immunoreactivity, and many typical plaques staining for Aß had little apoE immunoreactivity (Fig. 7.2).

Using a number of different antibodies, Aizawa et al38 found that an amino-terminal truncated apoE was the major form associated with senile plaques.

There is also some confusion as to the extent of apoE labeling of NFTs. Apolpoprotein E was not found in dystrophic neurites in early stages of NFT formation, suggesting it is probably not primarily involved in neurofibrillary pathology.32 Yamaguchi et al33 reported all extracellular NFTs were also positive for apoE—even those not positive for Ap, while Namba et al39 implied that only those NFTs having amyloid showed such staining. The staining of extracellular NFTs for apoE is somewhat less intense than the staining of senile plaques (Fig. 7.2).30

In normal brain, antibodies to apoE give widespread staining of the cell bodies and proximal dendrites of neurons.26,40 One report41 mentions an increased density in AD of olfactory receptor neurons staining for apoE. Neurons are also strongly stained with antibodies to the apoE receptor known as the low density lipoprotein receptor-related protein (LRP),31,42,43 while astrocytes are lightly stained.43 Neuronal staining for apoE is decreased in the cortex and hippocampus in AD,31 although apoE-immunoreactive neurites are closely associated with Ap-containing senile plaques.24 Senile plaques are strongly reactive with antibodies to the LRP.43

Another receptor for apoE, the very low density lipoprotein receptor, is normally also found on neurons, as well as on microglia—both resting and activated. But it occurs particularly on the activated microglia near senile plaques in AD.44

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