ALZHEIMER-DISEASE A68 PROTEINS INJECTED INTO RAT-BRAIN INDUCE CODEPOSITS OF BETA-AMYLOID, UBIQUITIN, AND ALPHA-1-ANTICHYMOTRYPSIN

Aberrantly phosphorylated tau proteins (i.e., A68 or PHF-tau) and beta -amyloid or A4 (betaA4) peptides are major components of pathologic le sions in Alzheimer disease (AD). Although A68 and betaA4 colocalize in AD neurofibrillary tangles (NFTs) and amyloid-rich senile plaques (SP s), the mechanisms leading to the convergence of A68, betaA4, and othe r proteins in the same AD lesions are unknown. To probe the biological properties of A68 in vivo, and to assess interactions of A68 with end ogenous proteins in the rodent brain, we injected A68, dephosphorylate d A68 (DEP-A68), and normal adult human tau protein into the hippocamp us and neocortex of rats. In marked contrast to DEP-A68 and tau, A68 r esisted rapid proteolysis and induced codeposits of three rodent prote ins-i.e., betaA4, ubiquitin, and alpha1-antichymotrypsin (ACT)-that ac cumulate in AD NFTs and SPs together with A68. These findings suggest that A68 may interact with betaA4, ubiquitin, and ACT in neuronal peri karya as well as in the extracellular space after release of A68 from degenerating neurons. The model system described here will facilitate efforts to elucidate mechanisms leading to the convergence of A68, bet aA4, ubiquitin, and ACT in hallmark lesions of AD.