The distribution of cells containing messenger RNA that encodes amyloid beta protein was determined in hippocampi and in various cortical regions from cynomolgus monkeys, normal humans, and patients with Alzheimer's disease by in situ hybridization. Both 35S-labeled RNA antisense and sense probes to amyloid beta protein messenger RNA were used to ensure specific hybridization. Messenger RNA for amyloid beta protein was expressed in a subset of neurons in the prefrontal cortex from monkeys, normal humans, and patients with Alzheimer's disease. This messenger RNA was also present in the neurons of all the hippocampal fields from monkeys, normal humans and, although to a lesser extent in cornu ammonis 1, patients with Alzheimer's disease. The distribution of amyloid beta protein messenger RNA was similar to that of the neurofibrillary tangles of Alzheimer's disease in some regions, but the messenger RNA was also expressed in other neurons that are not usually involved in the pathology of Alzheimer's disease.

We have mapped the neuroanatomical distribution of amyloid-fi-protein mRNA within neuronal subpopulations of the hippocampal formation in the cynomolgus monkey (Macaca fascicularis), normal aged human, and patients with Alzheimer disease. Amyloid-8-protein mRNA appears to be expressed in all hippocampal neurons, but at different levels of abundance. In the central nervous system of monkey and normal aged human, image analysis shows that neurons of the dentate gyrus and cornu Ammonis fields contain a 2.5-times-greater hybridization signal than is present in neurons of the subiculum and entorhinal cortex. In contrast, in the Alzheimer disease hippocampal formation, the levels of amyloid-fi-protein mRNA in the cornu Ammonis field 3 and parasubiculum are equivalent. These rmdings suggest that within certain neuronal subpopulations cell type-specific regulation of amyloid-,B-protein gene expression may be altered in Alzheimer disease.The hippocampal formation is a preferential site for the pathological appearance of neurofibrillary tangles (NFT) as well as amyloid deposition in neuritic plaques (NP) and cerebrovascular amyloidosis of Alzheimer disease (AD) (1)(2)(3)(4)(5). It now appears that these neuropathological markers all contain the same 4-kDa P peptide (6)(7)(8)(9). Recently, the amino acid sequence of the amyloid-P peptide has been used to identify cDNA clones of a 3.5-kilobase mRNA (10-13). The open reading frame of this mRNA predicts a polypeptide of 695 amino acids, which resembles a cell surface receptor (12) and contains the 4-kDa P peptide as part of a putative hydrophobic transmembrane domain (10-13). The expression of amyloid-,B-protein mRNA, in both normal and AD brain (10-14) as well as in nonneuronal tissues (11), suggests that the amyloid-,3-peptide precursor is a normal cellular protein, whose 4-kDa proteolytic cleavage product may accumulate during the neurodegenerative process of AD.The involvement of the amyloid-,/-protein gene in AD is suggested by genetic linkage analysis, mapping of the amyloid-13-protein gene on chromosome 21 at or near the locus responsible for familial AD (15), and the reported duplication of the gene in some cases of sporadic AD as well as karyotypically normal Down syndrome (16).In order to define precisely those cell types that specifically contain the amyloid-p-protein mRNA and thus may be involved in the aberrant deposition of the 4-kDa P peptide in AD, we have mapped the neuroanatomical distribution of the mRNA by in situ hybridization within neuronal subpopulations of the hippocampal formation in monkeys, normal aged humans, and patients with AD. Quantitation of the hybridization signal has allowed us to determine relative differences in the amount of amyloid-,B-protein mRNA between hippocampal neuronal subpopulations and to study the regulation of the mRNA during the disease process. Our results show that, although the amyloid-f3-protein gene is expressed widely in neurons of the hippocampal formation, differences are found in mRNA abundance between spec...

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