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At least 613 records · Page 34Linked to original sources
PubMed1993

A.E. Bennett Research Award 1993. Olfactory neuroblasts from Alzheimer donors: studies on APP processing and cell regulation.

Cell lines of continuously dividing human olfactory neuroblasts can be propagated using olfactory epithelium obtained from human donors at biopsy or autopsy. The expression of neuronal proteins in these cells, such as neurofilament protein and tau protein, can be increased using a combination of factors including nerve growth factor, fibroblast growth factor, interleukin 1 and interleukin 6. These cells also express aspects of human disease. Olfactory neuroblasts generated from donors with the common, sporadic forms of Alzheimer's disease, show elevated levels of the direct precursor to beta-amyloid, the amyloid precursor protein C-terminal derivative (CTD). When treated with the lysosomal inhibitor chloroquine, immunoblots of Alzheimer olfactory neuroblasts show seven-fold higher levels of CTDs than immunoblots from age-matched control neuroblasts. The disease related increases in CTDs can be reversed by treatment with agents that increase intracellular cyclic adenosine monophosphate (cAMP), such as dibutyryl-cyclic-AMP, theophylline, and isoproterenol.

Adenosine Monophosphate↗
PubMed1992

Spectrum of amyloid beta-protein immunoreactivity in hereditary Alzheimer disease with a guanine to thymine missense change at position 1924 of the APP gene.

We studied neuropathologically 3 patients of a previously unreported kindred of presenile Alzheimer disease (AD), characterized by a G to T mutation at base pair 1924 (695 transcript) of the amyloid precursor protein gene. Classic features of presenile AD are observed. Neurofibrillary tangles with paired helical filaments as well as neuritic plaques are found in large number in neocortex and hippocampus. beta-Protein deposits in meningeal and parenchymal vessels are present, but not severe. Prominent subpial ribbon-like deposits are detected with antibodies to a 28-residue synthetic peptide; however, only occasionally can they be seen in thioflavin S treated sections. Along with a mild involvement of vessels, as demonstrated by beta-protein immunolabeling, parenchymal involvement is also seen in the cerebellar molecular layer. In the course of the study, we have not detected neuropathologic changes, which are mutation specific. Further investigations of familial Alzheimer disease with known genetic mutations will clarify whether correlations exist between specific mutations and neuropathologic phenotypes.

Adult↗
PubMed1995

Beta APP mRNA transcription is increased in cultured fibroblasts from the familial Alzheimer's disease-1 family.

Familial (autosomal dominant) Alzheimer's disease (FAD) is a genetically heterogeneous disorder. Mutations in exons 16 and 17 of the amyloid beta-protein precursor (beta PP) gene currently account for less than 2% of FAD kindreds. No known defect in beta PP quantity, structure, or processing accounts for disease-associated beta-amyloid deposition in the majority of early-onset FAD kindreds. Only two out of a sample of 48 pedigrees (particularly the early onset FAD 4 kindred) contributed noticeably to evidence of linkage at the D21S16/13 and S1/S11 loci in the chromosomal region 21q21 [75]. Many early onset FAD pedigrees (including the FAD 1 and FAD 4 kindreds) show strong evidence of linkage to markers in the chromosome 14q24.3 region. Patients with trisomy 21 (Down's syndrome, DS) virtually always develop a histopathological phenotype indistinguishable from FAD, presumably on the basis of increased beta PP gene dosage and transcription. Whereas no beta PP gene duplication has been found in FAD, other mechanisms that augment beta PP production by effects at the transcriptional level could explain some FAD cases. Here, we report that cultured fibroblasts from affected members of the FAD 1 pedigree show a approximately 1.9 fold increase (P = 0.007) in beta PP mRNA levels compared to unaffected members when the cells are grown under stressed conditions in 0.5% serum. The elevated levels of beta PP mRNA in cells cultured in 0.5% serum also cosegregate with haplotypes in the 14q24.3 region when analyzed by linkage methods (LOD score = 3.26 at theta = 0.001). This is the chromosomal region to which FAD in this family has previously been mapped. As expected, fibroblasts from patients with DS used as a control show a similar beta PP mRNA increase. Fibroblasts from the FAD 4 pedigree did not show this defect under the conditions utilized here. beta PP and A beta protein levels were determined quantitatively after metabolic labeling and immunoprecipitation and found to increase 2.0 and 2.5 fold, respectively, in the fibroblasts from affected FAD 1 members. Finally, transient transfections of a beta PP promoter/chloramphenicol acetyl transferase reporter gene construct demonstrated a approximately 3-4 fold increase in beta PP promoter activity in affected fibroblasts from the FAD 1 but not the FAD 4 pedigree. Taken together, these data raise the possibility that an increase in beta PP transcription may underlie the AD phenotype in at least some of the chromosome 14-linked FAD families.

Alzheimer Disease↗
PubMed1993

Screening for the APP codon 670/671 mutations in Alzheimer's disease.

A mutation at codons 670 and 671 of exon 16 of the amyloid precursor protein has recently been identified as a cause of early onset familial Alzheimer's disease. Using restriction enzyme digestion, screening failed to reveal the occurrence of this mutation in 43 families with early onset, 31 families with late onset, 30 cases of sporadic Alzheimer's disease or 30 clinically normal individuals.

Adult↗
PubMed1982

Coexistence of somatostatin- and avian pancreatic polypeptide (APP)-like immunoreactivity in some forebrain neurons.

The indirect immunofluorescence technique was used to demonstrate the coexistence of somatostatin together with avian pancreatic polypeptide-like immunoreactivity within certain neurons of the rat forebrain. Numerous neurons containing these peptides were observed in the neocortex, hippocampus, olfactory tubercle, striatum, nucleus accumbens and lateral septum. In studies of serial sections stained alternately for these two peptides, and in restaining experiments, It could be determined that in many neurons in these areas these two peptides coexisted. In other brain areas such as the anterior periventricular hypothalamus, somatostatin cells were never found to contain avian pancreatic polypeptide-like immunoreactivity. Also, within the pancreas these two peptides were never found to coexist in the same cells. The findings represent a further example of the coexistence of more than one neuropeptide within a single neuron.

Animals↗
PubMed1995

beta-Amyloid precursor protein (beta APP) in human gut with special reference to the enteric nervous system.

The distribution of the beta-amyloid precursor protein (betaAPP) in the human gastrointestinal tract, from esophagus trough rectum, was studied using immunoblotting, as well as combined immunohistochemical and image analysis (optic microdensitometry) techniques. The study was focused on the enteric nervous system. betaAPP was detected by means of a monoclonal antibody (22C11), which recognizes all betaAPP isoforms as well as betaAPP-like proteins. Immunoblotting revealed two main protein bands, one corresponding to full-length betaAPPs (estimated molecular masses of approximately 97-115 kDa); the other corresponded to a protein with estimated molecular masses of 55 kDa. Specific betaAPP immunoreactivity (IR) was found in the submucous and myenteric plexuses localized in the supporting glial cells rather than in neurons. Differences were encountered neither in the localization nor in the intensity of immunostaining among different segments of the gastrointestinal tract. Moreover, no age-dependent changes were found. betaAPP IR was also regularly observed in blood vessels, primarily labelling endothelial cells. Our results provide evidence for the occurrence of betaAPP in human gastrointestinal tract of healthy people in both neuronal and nonneuronal tissues. Whether or not these findings have functional or clinical relevance remains to be clarified in future studies.

Adult↗
PubMed2006

Luteinizing hormone modulates cognition and amyloid-beta deposition in Alzheimer APP transgenic mice.

Until recently, the study of hormonal influences in Alzheimer disease was limited to the role of sex steroids. Despite numerous epidemiological studies supporting a protective role for estrogen in Alzheimer disease, recent studies show that estrogen administration in elderly women increases the risk of disease. Reconciling these contradictory reports, we previously hypothesized that other hormones of the hypothalamic-pituitary-gonadal axis, such as luteinizing hormone, may be involved in the onset and development of the disease. In this regard, luteinizing hormone is elevated in Alzheimer disease and is known to modulate amyloidogenic processing of amyloid-beta protein precursor. Therefore, in this study, to evaluate the therapeutic potential of luteinizing hormone ablation, we administered a gonadotropin-releasing hormone analogue, leuprolide acetate, to an aged transgenic mouse model of Alzheimer disease (Tg 2576) and measured cognitive Y-maze performance and amyloid-beta deposition after 3 months of treatment. Our data indicate that luteinizing hormone ablation significantly attenuated cognitive decline and decreased amyloid-beta deposition as compared to placebo-treated animals. Importantly, leuprolide acetate-mediated reduction of amyloid-beta correlated with improved cognition. Since both cognitive loss and amyloid-beta deposition are features of Alzheimer disease, leuprolide acetate treatment may prove to be a useful therapeutic strategy for this disease.

Alzheimer Disease↗