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 (beta A4) peptides are major components of pathologic lesions in Alzheimer disease (AD). Although A68 and beta A4 colocalize in AD neurofibrillary tangles (NFTs) and amyloid-rich senile plaques (SPs), the mechanisms leading to the convergence of A68, beta A4, and other proteins in the same AD lesions are unknown. To probe the biological properties of A68 in vivo, and to assess interactions of A68 with endogenous proteins in the rodent brain, we injected A68, dephosphorylated A68 (DEP-A68), and normal adult human tau protein into the hippocampus and neocortex of rats. In marked contrast to DEP-A68 and tau, A68 resisted rapid proteolysis and induced codeposits of three rodent proteins--i.e., beta A4, ubiquitin, and alpha 1-antichymotrypsin (ACT)--that accumulate in AD NFTs and SPs together with A68. These findings suggest that A68 may interact with beta A4, ubiquitin, and ACT in neuronal perikarya 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, beta A4, ubiquitin, and ACT in hallmark lesions of AD.
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, Philadelphia 19104-4283.
R W
RW
Shin
G T
GT
Bramblett
V M
VM
Lee
J Q
JQ
Trojanowski
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000302:isolation & purification; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D016874:Neurofibrillary Tangles; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014452:Ubiquitins / Q000302:isolation & purification; D000514:alpha 1-Antichymotrypsin / Q000302:isolation & purification; D016875:tau Proteins / Q000494:pharmacology
D016229:Amyloid beta-Peptides; C489131:Mapt protein, rat; D009419:Nerve Tissue Proteins; D014452:Ubiquitins; D000514:alpha 1-Antichymotrypsin; D016875:tau Proteins