Differential regulation of amyloid-beta-protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer disease.

Abstract

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...

The Functions of the Amyloid Precursor Protein Gene and Its Derivative Peptides: II Experimental Evidence and Clinical Studies

“…Other studies have suggested differences in neuronal subpopulation expression of APP mRNA [190]. An effect of age and anatomical region is supported by a study of cynomolgus monkeys in which APP 695 and 751 were increased 2 -7 times in the thalamus in 17-year-old monkeys when compared with 3-year olds [337].…”

“…The hydrophilic residues in Aβ contribute to the specificity of the interactions between Aβ peptides and may influence the transformation from a β pleated sheet structure to a random coil [187]. Aβ deposits are not found in rodent brain and this might relate to differences in the amino acid sequence between rodents, and other species-unknown factors independent of the primary structure might also influence fibril formation [188][189][190][191]. Amyloid structures in mammalian tissues might encourage covalent polymerization of reactive small molecules into larger molecules like melanin with cytoprotective properties.…”

Development of subcellular mRNA compartmentation in hippocampal neurons in culture

“…One study has reported the presence of the mRNA for amyloid precursor protein (APP) in the dendrites ofneurons in culture (Strong et al, 1990). Studies of APP mRNA distribution in tissue sections do not suggest a dendritic localization, however (Higgins et al, 1988;Lewis et al, 1988). There is also evidence that a nonmessenger RNA termed BCl is present in dendrites (Tiedge et al, 1991a,b).…”

An alternative polyadenylation of the β amyloid protein precursor mRNA regulates the translation

“…While the mechanism by which the OA4 peptide is generated from APP is unknown, overexpression of the APP in Alzheimer's disease has been proposed as a possible mechanism of APP metabolism disturbance Higgins et al, 1988;Palmert et al, 1988;Tanzi et al, 1988;Johnson et al, 1989Johnson et al, , 1990Neve et al, 1988Neve et al, , 1990. In this way, the 150% increase in APP gene expression in trisomy 21 might be related to the formation of the abundant senile plaques found in the cerebral cortex of Down's syndrome patients (Rumble et al, 1989 (Chirgwin et al, 1979).…”

“…In Alzheimer's disease, such a gene dosage effect has not been established (Podlisny et al, 1987). However, an increase in the expression of APP mRNA Higgins et al, 1988) or modifications in the differential expression of APP isoforms (Palmert et al, 1988;Johnson et al, 1989;Neve et al, 1988Neve et al, , 1990) have been reported in Alzheimer's disease.…”