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Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease
R E Tanzi1, A I McClatchey, E D Lamperti
1Neurogenetics Laboratory, Massachusetts General Hospital, Boston 02115.
Abstract:
Amyloid B-protein/amyloid A4 is a peptide present in the neuritic plaques, neurofibrillary tangles and cerebrovascular deposits in patients with Alzheimer's disease and Down's syndrome (trisomy 21) and may be involved in the pathogenesis of Alzheimer's disease. Recent molecular genetic studies have indicated that amyloid protein is encoded as part of a larger protein by a gene on human chromosome 21 (refs 6-9). The amyloid protein precursor (APP) gene is expressed in brain and in several peripheral tissues, but the specific biochemical events leading to deposition of amyloid are not known. We have now screened complementary DNA libraries constructed from peripheral tissues to determine whether the messenger RNA encoding APP in these tissues is identical to that expressed in brain, and we identify a second APP mRNA that encodes an additional internal domain with a sequence characteristic of a Kunitz-type serine protease inhibitor. The alternative APP mRNA is present in both brain and peripheral tissues of normal individuals and those with Alzheimer's disease, but its pattern of expression differs from that of the previously reported APP mRNA.
Insights
Researchers discovered a second amyloid precursor protein (APP) messenger RNA (mRNA) in both brain and peripheral tissues. This alternative APP mRNA, found in normal and Alzheimer's disease patients, has a different expression pattern.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyloid B-protein is implicated in Alzheimer's disease pathogenesis, found in plaques and tangles.
- The amyloid precursor protein (APP) gene on chromosome 21 encodes amyloid protein.
- The specific biochemical events leading to amyloid deposition remain unclear.
Purpose of the Study:
- To investigate if peripheral tissue APP mRNA is identical to brain mRNA.
- To identify alternative forms of APP mRNA and their characteristics.
Main Methods:
- Screening complementary DNA (cDNA) libraries from peripheral tissues.
- Analyzing messenger RNA (mRNA) sequences encoding amyloid precursor protein (APP).
Main Results:
- A second APP mRNA variant was identified, encoding an internal domain with Kunitz-type serine protease inhibitor sequence.
- This alternative APP mRNA is present in both brain and peripheral tissues.
- The expression pattern of the alternative APP mRNA differs from the previously known APP mRNA.
Conclusions:
- The existence of alternative APP mRNA transcripts suggests complex regulation of APP expression.
- Understanding these variants may offer new insights into Alzheimer's disease and Down's syndrome.
- Further research is needed to elucidate the functional significance of the Kunitz-type inhibitor domain in APP.