Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus.

Harvard University, Cambridge, Massachusetts, United States
Science (Impact Factor: 31.48). 03/1987; 235(4791):880-4. DOI: 10.1126/science.2949367
Source: PubMed

ABSTRACT The amyloid beta protein has been identified as an important component of both cerebrovascular amyloid and amyloid plaques of Alzheimer's disease and Down syndrome. A complementary DNA for the beta protein suggests that it derives from a larger protein expressed in a variety of tissues. Overexpression of the gene in brain tissue from fetuses with Down syndrome (trisomy 21) can be explained by dosage since the locus encoding the beta protein maps to chromosome 21. Regional localization of this gene by both physical and genetic mapping places it in the vicinity of the genetic defect causing the inherited form of Alzheimer's disease.

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    ABSTRACT: Alzheimer's disease (AD) is the gradual loss of the cognitive function due to neuronal death. Currently no therapy is available to slow down, reverse or prevent the disease. Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein (APP) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis. The AppBp1 pathway, also known as the neddylation pathway, activates the small ubiquitin-like protein nedd8, which covalently modifies and switches on Cullin ubiquitin ligases, which are essential in the turnover of cell cycle proteins. Here we discuss how APP may activate the AppBp1 pathway, which downregulates cell cycle markers and protects genome integrity. More investigation of this mechanism-driven hypothesis may provide insights into disease treatment and prevention strategies.
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    ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most frequent cause of dementia in elderly people. Current therapies are directed against the symptoms and at best slow down the progress of the disease in some cases. Thus, it is of particular importance to find drugs focusing on the origins of AD. Recent studies indicate that soluble oligomers (up to 12mers and higher) of Aβ1−42 are highly neurotoxic at nanomolar levels and probably a major cause for the symptoms of AD. Furthermore, structural similarity was found between the oligomers of several amyloidogenic proteins. A compound that inhibits Aβ aggregation in AD may therefore prevent aggregation in other amyloid diseases as well, with little or no modification to the compounds. These findings indicate that inhibition of oligomer aggregation is an appealing approach for AD drug research. In this study, we show the effects of a library of 18 chemical compounds, based on a 2-pyridone structure which is known to interfere with Aβ assembly, on the formation of oligomers. These molecules fulfil Lipinski’s rule of 5 and thereby should readily pass the blood brain barrier after application. Oligomers of Aβ1−42 were prepared in the absence and presence of these compounds and identified using Western blotting, dot blotting and atomic force microscopy. The toxicity of these preparations was determined by applying them onto neural cell lines and measuring the cell viability with MTT, WST-1 and resazurin based assays. The results indicate that several compounds decreased neurotoxicity of the oligomeric preparations by inhibition of aggregation. Despite the high variation in toxicity between the individual preparations we identified a compound offering both, low toxicity and stable oligomerization inhibiting potency, which will serve as a lead molecule for further development. Also we demonstrate an impact of the applied oligomerization protocol on cell viability. After further optimization we hope our method will prove to be a useful method for screening drug candidates directed against Aβ oligomers.
    09/2007, Degree: Magister rer. nat., Supervisor: Johannes Berger
  • The FASEB Journal 01/2000; 14(12):1837-1847. DOI:10.1096/fj.99-0938com · 5.48 Impact Factor