APP MRNA DYSREGULATION AND ALZHEIMERS DISEASE

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DESCRIPTION The accumulation of AB protein in the central nervous system remains a hallmark of Alzheimer's Disease (AD). AB is proteolytically cleaved from the amyloid precursor protein (APP) which itself is over-expressed in neurons, glia and possibly peripheral cells and tissues. Patients with Down's Syndrome carry an extra APP allele, overexpress APP mRNA by 1.5-2 fold, deposit extracellular AB and inevitably develop AD. Recently, a family with autosomal dominant, early onset AD (EOAD) was identified with increased APP gene transcription and 1.6 fold normal, steady state APP mRNA levels. While it remains controversial, APP gene mRNA is likely over-expressed by 1.2-2 fold in CNS neurons of a subset of late onset AD patients as compared to age matched controls. Therefore, APP mRNA levels and the cellular mechanisms which control them are likely important in AD pathogenesis. The applicant has recently shown that APP mRNA stability is controlled by the regulated interactions of a 29 base, 3' untranslated region destabilizing element and two mRNA binding proteins, nucleolin and hnRNP C protein. The 29 base element is found in all amyloidogenic APP mRNAs as well as the murine homologue and destabilizes APP mRNA in resting cells. After cell stimulation, nucleolin and hnRNP C are activated, bind APP mRNA, causing its stabilization and accumulation. The applicant has also shown that small differences in APP mRNA content due to variable stability cause significant increases in APP production. Therefore, it is proposed that modest increases in APP mRNA content comparable to that seen in DS, an EOAD kindred and some AD patients can have significant effects on APP production. The applicant proposes to test the hypothesis that "increased APP production in part depends on APP mRNA stability which in turn is controlled by interactions between the 29 base element and hnRNP C and nucleolin." This will be tested by the studies (i) to identify the spatial organization and nucleotide sequence of the 29 base element regulating the decay of APP mRNA, (ii) to characterize how hnRNP C and nucleolin are activated to bind to APP mRNA, and (iii) determine the effects of APP mRNA stability and steady state levels on AP synthesis. Taken together, these studies will investigate the underlying mechanisms of APP mRNA posttranscriptional gene regulation and its consequences on APP and AB production.