REVERSAL BY DESFERRIOXAMINE OF TAU-PROTEIN AGGREGATES FOLLOWING 2 DAYS OF TREATMENT IN ALUMINUM-INDUCED NEUROFIBRILLARY DEGENERATION IN RABBIT - IMPLICATIONS FOR CLINICAL-TRIALS IN ALZHEIMERS-DISEASE

\A clinical trial in patients with Alzheimer's disease has indicated t hat frequent intramuscular (i.m.) treatment with desferrioxamine (DFO) slows progression of the disease. Confirmatory trials have not been c arried out, partly because of the rigors of twice daily intramuscular injections over a period of 2 years, even though the initial report ga ve promising results. The aim of the present study was to determine an optimal DFO treatment protocol in an animal model exhibiting Alzheime r's-like intraneuronal protein aggregates, previously shown to be part ially reversed by such treatment. New Zealand white rabbits were injec ted intracisternally with either aluminum (Al) maltolate or with salin e on day 0. Intramuscular injections of DFO were given to selected rab bits for 2 days prior to sacrifice on days 4, 6 or 8. Bielschowssky's silver impregnation demonstrated widespread neurofibrillary degenerati on (NFD) in neuronal cell bodies and neurites of brain and spinal cord from Al-treated rabbits. Monoclonal antibodies Tau-2 AT8, PHF-I and A lz-50, all of which characteristically stain neurofibrillary tangles a ssociated with Alzheimer's disease, strongly labeled the Al-induced NF D. The number of positive neurons and staining intensities were much l ess in rabbits treated with Al and subsequently with DFO, than in anim als only given Al. Control rabbits receiving intracisternal saline wer e negative for NFD. The results of quantitative immunohistochemistry u sing image analysis confirmed that immunostaining densities with all t au mAbs were higher in Al-treated than in Al-DFO-treated or in saline- treated controls. Furthermore, it appears that hyperphosphorylation of tau does not make this protein resistant to degradation once Al has b een removed by DFO treatment. The effectiveness of only two days of DF O treatment in reversing Al-induced neurofibrillary degeneration sugge sts that further clinical trials of DFO for treatment of Alzheimer's d isease should be attempted using much less frequent administration of DFO than in the initial study. (C) 1998 Intox Press, Inc.