Direct sequencing of DNA from a family with autopsy-proven Alzheimer's disease revealed a single amino acid substitution (Phe for Val) in the transmembrane domain of the amyloid precursor protein.
Using protease inhibitory functional assays, we show that both the 105-kDa and 120-kDa APP proteins in normal and Alzheimer disease brain contain the KPI domain.
The amyloid forming beta-peptide of Alzheimer's disease is synthesized as part of a larger integral membrane precursor protein (beta APP) of which three alternatively spliced versions of 695, 751, and 770 amino acids have been described.
In the present report, we demonstrate that a specific spliced form of mRNA that is transcribed from the APP gene and that lacks the beta/A4 sequence is elevated in the nucleus basalis, occipitotemporal cortex, and parahippocampal gyrus in Alzheimer's disease brain relative to controls.
If this twofold increase in the APP-751 mRNA/APP-695 mRNA ratio results in a corresponding increase in the APP-751/APP-695 protein ratio, this would support the hypothesis that impaired proteolysis promotes the accumulation of abnormal proteins in the brain during AD.
Considering hippocampal neuron loss and cortical neuron loss and atrophy, the data presented may be compatible with increased APP-751 mRNA and decreased APP-695 mRNA prevalence in remaining neurons in AD.
Understanding the processing of the beta-amyloid precursor protein and the origin of beta-amyloid deposits should provide insights into a potentially seminal feature of cortical degeneration in Alzheimer's disease.
Polypeptide (A4), which is derived from a larger precursor membrane protein (beta APP), is an important component of brain amyloid in Alzheimer's disease.
The regulation of extracellular proteolysis by PN-II and the deposition of at least parts of the molecule in senile plaques is consistent with previous reports that implicate altered proteolysis in the pathogenesis of Alzheimer's disease.
Whereas in Down's syndrome, over-expression of the gene coding for PreA4 is likely to be responsible for the premature development of cerebral amyloidosis, a similar mechanism is yet to be demonstrated in Alzheimer's disease.
To study the putative precursor proteins (PreA4(695), PreA4(751), and PreA4(770] of Alzheimer's disease A4 amyloid protein, polyclonal and monoclonal antibodies were raised against a recombinant bacterial PreA4(695) fusion protein.
Sequence analysis of the various clones revealed 16 exons to encode the 695 residue precursor protein (PreA4(695] of Alzheimer's disease amyloid A4 protein.
Recently, it has been suggested that Alzheimer's disease is associated with a duplication of the amyloid precursor protein gene localized to chromosome 21q21.
These results suggest that APP gene expression is highly regulated in normal tissue, that many different cell classes in brain express the APP gene, and that neuronal expression may increase specifically in brain regions where widespread injury occurs in AD.
Using an oligonucleotide probe, we isolated cDNA clones corresponding to the precursor of the beta-amyloid peptide (BAP) from brain libraries of 3 patients with sporadic Alzheimer's disease (AD).