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Recent reports describe successful treatment using copper chelation therapy in neurodegenerative animal models. However, the success claimed for chelation therapy in neurodegenerative diseases is still rather controversial. To acquire new information on copper metabolism/homeostasis, we utilized cuprizone, a very sensitive and selective copper-chelating agent with well-known neurotoxic properties, as a relevant chemical model in mice. Upon cuprizone treatment, mice developed a pronounced astrocytosis, with brain oedema and spongiosis characterised by vacuolisations of the neuropil predominantly in the white matter. In addition, cuprizone treatment severely altered copper and zinc homeostasis in the central nervous system (CNS) as well as in all other tissues examined, with increasing metal ion concentrations particularly in the CNS. Concomitant with this increase in the Cu and Zn concentration in the brain, metallothionein-I and -II were also highly immunoreactive in astrocyte, consistent with the astrocytosis and demyelination observed in our and other laboratories.

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To report an ataxic variant of Alzheimer disease expressing a novel molecular phenotype.Design: Description of a novel phenotype associated with a presenilin 1 mutation. Setting:The subject was an outpatient who was diagnosed at the local referral center.Patient: A 28-year-old man presented with psychiatric symptoms and cerebellar signs, followed by cognitive dysfunction. Severe ␤-amyloid (A␤) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral cortex and by Purkinje cell dendrite loss in the cerebellum. A presenilin 1 gene (PSEN1) S170F mutation was detected. Main Outcome Measures:We analyzed the processing of A␤ precursor protein in vitro as well as the A␤ species in brain tissue. Results:The PSEN1 S170F mutation induced a 3-fold increase of both secreted A␤ 42 and A␤ 40 species and a 60% increase of secreted A␤ precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N-terminally truncated A␤ species ending at both residues 40 and 42. Conclusion:These findings define a new Alzheimer disease molecular phenotype and support the concept that the phenotypic variability associated with PSEN1 mutations may be dictated by the A␤ aggregates' composition.

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