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
J. Savory et al., 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, Neurotoxicology, 19(2), 1998, pp. 209-214
\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.