ABSTRACT
OBJECTIVE: To test the hypothesis that use of antihypertensive medication is associated with lower Alzheimer disease (AD) neuropathology. METHODS: This was a postmortem study of 291 brains limited to those with normal neuropathology or with uncomplicated AD neuropathology (i.e., without other dementia-associated neuropathology) in persons with or without hypertension (HTN) who were and were not treated with antihypertensive medications. Neuritic plaque (NP) and neurofibrillary tangle (NFT) densities, quantified in selected brain regions according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathologic criteria, with additional cortical NP counts, yielded 24 neuropathologic regional measures or summaries. Medicated hypertension (HTN-med; n = 77), nonmedicated HTN (HTN-nomed; n = 42), and non-HTN (no-HTN; n = 172) groups were compared by analyses of variance. RESULTS: The HTN-med group had significantly less neuropathology than the no-HTN group. The no-HTN group averaged over 50% higher mean NP and NFT ratings, and double the mean NP count, of the HTN-med group. The HTN-nomed group had significantly more neuropathology than the HTN-med group, but not significantly less than the no-HTN group. CONCLUSIONS: There was substantially less Alzheimer disease (AD) neuropathology in the medicated hypertension group than the nonhypertensive group, which may reflect a salutary effect of antihypertensive medication against AD-associated neuropathology.
Subject(s)
Alzheimer Disease/pathology , Antihypertensive Agents/therapeutic use , Dementia/pathology , Hypertension , Aged , Aged, 80 and over , Blood Pressure/physiology , Brain/anatomy & histology , Brain/pathology , Female , Humans , Hypertension/drug therapy , Hypertension/physiopathology , Neurofibrillary Tangles/pathology , Plaque, Amyloid/pathology , Risk FactorsABSTRACT
The rat Crisp-1 gene encodes Protein DE (acidic epididymal glycoprotein; AEG), a glycoprotein secreted by the epididymal epithelium that associates with maturing sperm and has been implicated in the process of sperm-egg fusion. Previous characterization of the Crisp-1 messenger RNA in the rat epididymis has demonstrated the presence of 3 splice variants (Klemme et at, 1999). This study was undertaken to determine if expression of the Crisp-1 splice variants in the rat epididymis is region-specific and correlates with the region-specific pattern of synthesis of the D and E forms of the Crisp-1 protein. Expression of each of the splice variants was shown by RNase protection assays to be under the control of androgens, but they are not differentially regulated either within the epididymal segments or along the length of the organ. The reported structure of the mouse Crisp-1 gene does not include an exon that is equivalent to the rat exon 1, suggesting that the rat splice variants cannot exist in the mouse and may be specific to the rat. Furthermore, the mouse transcription start site is situated in a different region of the gene than in the rat. In this study, a comparison of the mouse and rat genes in the region flanking the mouse exon 1 and the rat exon 2 (within the rat intron 1) shows greater than 80% sequence identity, including the conservation of several putative androgen receptor binding sites. In addition, the rat gene is shown to have a corrupted TATA box in intron 1 that corresponds to the TATA box located in the mouse gene. These observations explain the preferential transcription for the mouse gene in this region, while the predominant start site for the rat gene is 5' of the upstream exon 1. Although an exon corresponding to the rat exon 1 has not been found in the mouse gene, reverse transcription-polymerase chain reaction experiments using mouse epididymal RNA suggest that such an exon exists in the mouse gene and is transcribed at low frequency.
Subject(s)
Alternative Splicing/genetics , Epididymis/physiology , Metalloproteins/genetics , Testicular Hormones/genetics , Animals , Base Sequence , Cloning, Molecular , Epididymal Secretory Proteins , Exons , Gene Expression Regulation/genetics , Introns , Male , Mice , Mice, Inbred Strains , Molecular Sequence Data , RNA, Messenger/analysis , Rats , Rats, Sprague-Dawley , Regulatory Sequences, Nucleic Acid/genetics , Reverse Transcriptase Polymerase Chain Reaction , Species Specificity , Transcription, Genetic/geneticsABSTRACT
Rat androgen-regulated acidic epididymal glycoprotein (AEG), also known as Protein DE, is a product of the Crisp-1 gene. Protein DE is secreted into the epididymal lumen and binds to sperm heads during their transit through the epididymis. In experiments reported here, the rat Crisp-1 gene has been cloned and its structure determined. The rat Crisp-1 gene spans 38kb and contains nine exons encoding an 1120bp epididymal Protein DE mRNA. The boundaries of the protein-coding exons are structurally organized similar to the mouse Crisp-1 gene, except for the 5' untranslated sequence, which is encoded by one exon in the mouse Crisp-1 gene and two exons in the rat gene. All the introns are flanked by AG/GT consensus splice sequences. Crisp-1 is a single-copy gene as shown by the presence of single bands by Southern blot analysis and PCR using rat genomic DNA as template. Recognition sites for steroid hormone receptors are present in the 5' flanking region and in intron 1, consistent with the known regulation of Protein DE expression by androgens. RT-PCR experiments demonstrate three splice variant mRNAs involving the non-coding exon 2. The Crisp-1 gene also produces an mRNA without an exon 1 sequence by utilizing a transcription start site in intron 1, 5' of the start of exon 2. All forms of the Crisp-1 mRNA are predicted to encode Protein DE.
