Amyloid A4 Protein and Its Precursor in Down's Syndrome and Alzheimer's Disease

Abstract

In patients with Alzheimer's disease, amyloid fibrils that are aggregates of A4 protein subunits are deposited in the brain. A similar process occurs at an earlier age in persons with Down's syndrome. To investigate the deposition of amyloid in these diseases, we used a radioimmunoassay to measure levels of the amyloid precursor (PreA4) in the serum of 17 patients with Down's syndrome, 15 patients with Alzheimer's disease, and 33 normal elderly controls. The mean (+/- SD) concentration of serum PreA4 was increased 1.5-fold in patients with Down's syndrome (2.49 +/- 1.13 nmol per liter) as compared with that in controls (1.68 +/- 0.49 nmol per liter; P less than 0.007); the levels in patients with Alzheimer's disease were similar to those in controls (1.83 +/- 0.78; P less than 0.98). We also found that the concentration of PreA4 in the brain tissue of two adults with Down's syndrome (100 and 190 pmol per gram) was higher than that in the brain tissue of either 26 patients with Alzheimer's disease (64.4 +/- 17.3 pmol per gram) or 17 elderly controls with neurologic disease (68.5 +/- 26.3 pmol per gram). Immunocytochemical studies of brain tissue from 26 patients with Down's syndrome showed that the deposition of A4 protein amyloid began in these patients approximately 50 years earlier than it began in 127 normal aging subjects studied previously, although the rate of deposition was the same. We conclude that, since the gene for PreA4 is on the long arm of chromosome 21, which is present in triplicate in Down's syndrome, overexpression of this gene may lead to increased levels of PreA4 and amyloid deposition in Down's syndrome. However, since increased levels of PreA4 are not present in Alzheimer's disease, additional factors must account for the amyloid deposition in that disorder.

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

“…We next determined that total APP levels did not increase with age leading to the observed increases in insoluble Aβ in DS, which is consistent with previous reports [13,69] despite individuals with DS having higher APP levels than controls [52]. This led us to the hypothesis that the activity of enzymes involved with the cleavage of APP may shift with age to favor the production of amyloidogenic fragments [10,56,57].…”

“…In the most common form of DS, trisomy 21, three copies of chromosome 21 (21q21.2) leads to the overexpression of APP in brain and in peripheral lymphocytes [47,52]. As a consequence, plasma Aβ is significantly higher in individuals with DS (17-58 years) than in age-matched controls [8,38,55].…”

“…Senile plaques contain the β-amyloid peptide that is derived from a longer precursor protein, β-amyloid precursor protein (APP), the gene for which is on chromosome 21. In the most common form of DS, trisomy 21, chromosome 21 (21q21.2) is present in triplicate and leads to overexpression of APP [52]. However, despite life-long overexpression of APP in brain and in peripheral lymphocytes [47,52], Aβ accumulation in plaques does not typically begin until after the age of 30 years [35].…”

“…In the most common form of DS, trisomy 21, chromosome 21 (21q21.2) is present in triplicate and leads to overexpression of APP [52]. However, despite life-long overexpression of APP in brain and in peripheral lymphocytes [47,52], Aβ accumulation in plaques does not typically begin until after the age of 30 years [35]. However, Aβ within diffuse plaques and compact plaques has also been observed occasionally in the temporal cortex of individuals under 40 years (i.e.…”

A GG Nucleotide Sequence of the 3′ Untranslated Region of Amyloid Precursor Protein mRNA Plays a Key Role in the Regulation of Translation and the Binding of Proteins

“…These different posttranscriptional controls of APP mRNA translation and stability could be of importance, since the overproduction of APP could be related to the development of the characteristic neuropathological lesions of Alzheimer's disease (35). Such an overproduction of APP has been well documented in Down's syndrome patients and is related to the trisomy of the chromosome 21, which carries the APP gene.…”