Aluminum and Alzheimer's Amyloid Beta Protein
  
Dr. Masahiro Kawahara

 Amyloid beta-protein (AßP) is the major component of senile plaques of the Alzheimer's brain, composed of 39~43 amino acid peptides derived from amyloid precursor proteins (APPs). It is widely believed that neurotoxic effects of AßP is related to the etiology of Alzheimer's disease. Furthermore, monomeric AßP has a strong tendency to aggregate forming insoluble polymeric complexes. Its neurotoxicity was reported to be enhanced by the aggregation. Thus, the factors which promote or inhibit the aggregation of AßP may play a key role in the amyloid deposition, and finally, to the etiology of Alzheimer's disease.

We have investigated the effects of trace metals including (Al), (Zn), (Cu), (Fe), (Cd) on the aggregation of AßP using gel-electrophoresis and immunoblotting. In the pre-treated AßP solution with Al, the aggregation of AßP was strikingly enhanced and the appearance of much higher molecular weight polymers were observed. Other metals including Zn, Fe, Cu, Cd caused a small degree of aggregation compared to Al. There were no significant changes in the pre-treatment solutions with calcium or magnesium. Dose-dependent enhancement of the aggregation by aluminium was observed. Furthermore, cultured rat cortical neurons were applied AßP and stained by anti-AßP after 4 days to observe the deposition of amyloid fibrils on membrane surfaces. Al-treated AßP showed a remark able, fibrillar deposition compared to the control.

Our results revealed that Al caused the remarkable aggregation and the deposition of AßP. Therefore, it is suggested that Al, accumulated in the brain, may provide a "seed" for the nucleation process of the aggregation of AßP and accelerate the aggregation of AßP, and eventually, enhanced the neurotoxicity of AßP.

References

 

For further information:

Dr Masahiro Kawahara
Dept.of Mol. & Cell. Neurobiology
Tokyo Metropolitan Institute for Neuroscience
Musashidai 2-6, Fuchu-shi, Tokyo 183,
JAPAN

Tel (423)25-3881
Fax (423)21-8678
Mail to: kawamasa@tmin.ac.jp


Journal of Chemical Neuroanatomy 15 (1998) 21-60
Pamela Zambenedetti, Renzo Giordano, Paolo Zatta.

Metallothioneins (MTs) represent a group of intra-cellular, low molecular weight, cysteine-rich and ubiquitous proteins (Margoshes and Vallee, 1957). Human MTs are encoded by a complex multigene family located on chromosome 16, which includes two functional MT-I genes and a functional MT-II gene (Schmidt et al., 1984). The physiological functions of MTs are not yet fully defined. In brain, MTs are expressed in three isoforms, MT-I, MT-II and MT-III. MT-I and MT-II were identified immunohistochemically in the pia mater, ependymal cells, astrocytes, glial processes and fibrous astrocytes in the white matter in the telencephalon. They appear to be totally absent in neurons, oligodendroglia and microglia in all areas of the brain (Suzuki et al., 1994). In the cerebellum, MTs were detected in the Bergmann glial cells, in protoplasmic astrocytes of the granular layer and in fibrous astrocytes of the white matter (Suzuki et al., 1994). In experimental animals, MT-I is more significantly induced in those brain areas that are usually involved in the stress response (Hidalgo et al., 1991). In contrast, MT-III, appears to be expressed exclusively in neurons (Uchida et al., 1991; Palmiter et al., 1992; Uchida, 1994; Chen et al., 1996), especially the zinc-containing neurons of the hippocampus, and appears to be absent from glial cells (Aschner, 1996).

One of the neuropathological characteristics of Alzheimer's disease is the presence of a large number of reactive astrocytes, often, but not always, associated with senile plaques. The factors responsible for such an activation are as yet totally unknown. Other characteristic features of this disease such as ßA4 amyloid accumulation, senile plaques and neurofibrillary tangles represent well known pathological phenomena. Some studies suggest that ßA4 plays a major role in the reactive astrocytosis characteristic of Alzheimer's disease. In the normal human brain, metallothionein isoforms I and II are expressed in astrocytes but not in neurons. In the present study, we used anti-metallothionein antibodies to detect cells expressing metallothioneins isoforms I and II in normal and Alzheimer's disease (AD) brain sections. Results showed that expression of these proteins in the cortex, cerebral white matter and cerebellum is a relevant anatomopathological characteristic of Alzheimer's disease. Analysis of Alzheimer's disease brain sections revealed high expression of metallothioneins I/II in astrocytes and microcapillaries, and in the granular but not the molecular layer of the cerebellum. Furthermore, metallothionein expression can be used as a marker to identify subtypes of astrocytes.

References:

Margoshes, M., Vallee, B.L., 1957. A cadmium protein from equine imaging hyperintensity in Alzheimer's disease: correlation with  kidney cortex. J. Am. Chem. Soc. 79, 4813-4814.

Schmidt, C.J., Hamer, D.H., McBride, O.W., 1984. Chromosome location and human metallothionein genes: implications in Menkes' disease. Science 224, 1104-1106.

Suzuki, K., Nakajiama, K., Otaki, N., Kimura, M., Kawaharada, U., Uehara, K., Hara, F., Nakazato, Y., Takatama, M., 1994. Localization of metallothionein in aged human brain. Pathol. Int. 44, 20-26.

Hidalgo, J., Chapmany, L., Marti, O., Armario, A., 1991. Metallothionein-I induction by stress in specific brain areas. Neurochem. Res. 16, 1145-1148.

Uchida, Y., Takio, K., Titani, K., Ihara Y., Tomonaga, M., 1991. The growth inhibitory factor that is deficient in Alzheimer's disease a 68 amino acid metallothionein-like protein. Neuron 7, 337-347.

Palmiter, R. D., Findley, S. D., Whitemore, T. E., Durnam, D. M., 1992. MT-III, a brain specific member of the metallothionein family. Proc. Natl. Acad. Sci. USA 89, 6333-6337.

Uchida, Y., 1994. Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative disease. Biol. Signals 3, 211-215.

Chen, C.-F., Wang, S.-H., Lin, L.-Y., 1996. Identification and characterization of metallothionein III (Growth Inhibitory Factor) from porcine brain. Comp. Biochem. Physiol. 115B, 27-32.

Aschner, M., 1996. The functional significance of brain metallothioneins. FASEB J. 10, 1129-1136.

 




 

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