Senile dementia of the Alzheimer type (SDAT) is characterized by severe memory loss and specific brain lesions which include cell death, intracellular paired helical filaments, amyloid plaques, and vascular plaques. A number of different mechanisms have been proposed to account for the genesis of these lesions including: 1) the death of dysfunction of specific projection neurons; 2) changes in the levels of hormones or trophic factors; 3) leakage of foreign proteins into brain via primary vascular lesions; 4) genetic alterations perhaps similar to those in Down's Syndrome where SDAT lesions occur in middle age; 5) changes in the immune system; and 6) viral infections. We will test each of these hypotheses in SDAT and Down's brain by determining by slot blot analysis, in situ hybridization, cell-free translation, and screening of recombinant DNA libraries.

I. The levels of total ribosomal RNA, polyadenylated RNA, and specific abundant mRNAs in relevant brain areas and cell types with and without overt pathology.

II. The levels of neurotransmitter related mRNAs as well as mRNAs encoding hormone precursors and neural trophic substances.

III. Which RNA sequences are expressed at different levels or are unique to SDAT brain.

IV. The source of amyloid proteins in brain.

V. If lymphoid cells or immune factors are present in brain.

VI. If specific viral sequences are uniquely present in brain.

The successful completion of these studies will for the first time characterize SDAT at the molecular level, possibly pinpointing heretofore unknown transcriptional changes of primary importance in the etiology of this disease.

R01AG005537

1985-02-01

1988-11-30