Specificity to Alzheimers Disease

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Upregulation of clusterin and abnormal staining of lesions for apoE is not limited to AD. Brain levels of clusterin seem to be elevated in many conditions involving injury or chronic inflammation of the brain. Elevated levels of the mRNA for clusterin are seen in the hippocampus in Pick's disease as well as in AD.4 Abnormal staining for clusterin has been seen in dystrophic neurites and some NFTs in the Parkinson's dementia complex of Guam (Fig. 7.1). It has also been seen in humans in ischemic Purkinje cells which showed the shrunken and pyknotic appearance characteristic of irreversible damage.45 Intense staining for clusterin has been seen in hypertrophic astrocytes in cases of multiple sclerosis, stroke and AIDS encephalitis. In these cases, however, the distribution of clusterin did not appear to correlate with that of the MAC,46 a correlation which does appear to occur in AD.9

Clusterin levels in rat brain neurons appear to increase with aging,47 while the increased levels seen after experimental lesions seem to be in both neurons and astrocytes. Perforant path transection led to the appearance of clusterin in scattered hippocampal neurons as well as extracellularly.48 Excitotoxic lesions of the hippocampus led to a marked increase in the number of clusterin-immunopositive pyramidal neurons within the degenerating CA3 and CA4 pyramidal cell layer6,49 and to an overexpression of the clusterin mRNA.15,49 The overexpression of the mRNA appeared to involve reactive astrocytes. Glutamate treatment of primary hippocampal cell cultures49 or cultures of embryonic rat spinal cord50 also induced increases in clusterin mRNA. Abnormally high levels of the mRNA have also been reported in scrapie-infected hamster brain4 but the type of cell involved was not identified. Treatment of animals with the toxic ricin resulted in upregulation of clusterin in reactive astrocytes and in the axotomized motoneurons.51 Complete cerebral ischemia in the rat led to the accumulation of both apoE and clusterin in neurons exhibiting signs of ischemic damage and in multiple extracellular deposits located close to the microvessels.52

Apolpoprotein E staining has been found associated with the amyloid in various types of human cerebral or systemic amyloidosis,53,54 including the kuru plaques in CreutzfeldtJakob disease,39 and with the mainly extracellular NFTs and occasional diffuse Ap deposit in the Parkinson's dementia complex of Guam.30,55 As in AD, not all of the tau-positive tangles were also stained for apoE.55 A comparison of staining for Ap and apoE in AD and the Parkinson's dementia complex is shown in Figure 7.2.

Apolpoprotein E immunoreactivity has also been reported in a few percent of the Pick's bodies in the brains of two patients with Pick's disease. Apolpoprotein E-positive inclusions were limited to limbic areas such as the dentate gyrus.56

Nor is the colocalization of apoE with amyloid deposits limited to humans. In aged monkeys,57,58 chimpanzees,59 dogs60 and Microcebus murinus61 apoE is found colocalized with amyloid beta protein in senile plaques and blood vessels. In the last named species, astrocytes and some neurons are also immunostained for apoE, suggesting further parallels to the human.

Upregulation of apoE is also found in astrocytes in a mouse model of scrapie where the increase occurs soon after the amyloid-forming abnormal form of the prion protein accumulates in astrocytes.18 An increased abundance of apoE mRNA in astrocytes close to neuronal cell bodies, similar to that seen in AD, has been observed in the hippocampus of rats with unilateral ablation of the entorhinal cortex.19

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