Shigeo Kakimi

Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer's disease.

Aluminum (Al) exposure has been reported to be a risk factor for Alzheimers disease (senile dementia of Alzheimer type), although the role of Al in the etiology of Alzheimers disease remains controversial. We examined the presence of Al in the Alzheimers brain using energy-dispersive X-ray spectroscopy combined with transmission electron microscopy (TEM-EDX). TEM-EDX analysis allows simultaneous imaging of subcellular structures with high spatial resolution and analysis of small quantities of elements contained in the same subcellular structures. We identified senile plaques by observation using TEM and detected Al in amyloid fibers in the cores of senile plaques located in the hippocampus and the temporal lobe by EDX. Phosphorus and calcium were also present in the amyloid fibers. No Al could be detected in the extracellular space in senile plaques or in the cytoplasm of nerve cells. In this study, we demonstrated colocalization of Al and beta-amyloid (Abeta) peptides in amyloid fibers in the cores of senile plaques. The results support the following possibilities in the brains of patients with Alzheimers disease: Al could be involved in the aggregation of Abeta peptides to form toxic fibrils; Al might induce Abeta peptides into the beta-sheet structure; and Al might facilitate iron-mediated oxidative reactions, which cause severe damage to brain tissues.

Familial parkinsonism and dementia with ballooned neurons, argyrophilic neuronal inclusions, atypical neurofibrillary tangles, tau-negative astrocytic fibrillary tangles, and Lewy bodies

Abstract We report four patients with a new type of familial parkinsonism and dementia consisting of an autosomal dominant inheritance, dopa-responsive parkinsonism, severe dementia, variable myoclonus and autonomic disturbances. Autopsy of two patients revealed symmetrical cerebral atrophy with fronto-temporal dominant distribution, and marked depigmentation in the substantia nigra and locus ceruleus. Neuronal loss and gliosis were observed in the deep cerebral cortex and amygdala as well as in the areas vulnerable to Parkinson’s disease. In the cerebral cortex, swollen neurons with frequent granulovacuolar changes were observed, consisting of ballooned neurons and those with argyrophilic intracytoplasmic inclusions, in addition to neuropil threads. Atypical neurofibrillary tangles, which barely stained with tau antibodies, were numerous in the upper cortical layers, consisting of 15-nm straight tubules. In addition, tau-negative astrocytic fibrillary tangles were also frequent. Electron microscopically, the ballooned neurons and argyrophilic neuronal inclusions contained filamentous structures coated with fuzzy electron-dense deposits. The inclusions showed immunohistochemical features different from those of cortical Lewy bodies and Pick bodies. Occasional Lewy bodies were present in the brain stem lesions of both patients. In two of our patients, the pathology in the brain stem was similar to that of Parkinson’s disease, whereas their cerebral pathology was unusual and has not been reported previously.

26Al incorporation into the brain of suckling rats through maternal milk.

Aluminium inhibits prenatal and postnatal brain development. However, aluminium incorporation into the brain of sucklings through maternal milk has not yet been well clarified because aluminium lacks a suitable isotope for radioactive tracer experiments. Using 26Al (26AlCl(3)) as a tracer, we measured 26Al incorporation into the brain of suckling rats by accelerator mass spectrometry. Lactating rats were subcutaneously injected with 26AlCl(3) from day 1 to day 20 postpartum. Suckling rats were weaned from day 21 postpartum. From day 5 to day 20 postpartum, the amounts of 26Al measured in the cerebrum, cerebellum, spinal cord, liver, and kidneys of suckling rats increased significantly. After weaning, the amounts of 26Al in the liver and kidneys decreased remarkably. Alternatively, in the cerebrum, cerebellum, and spinal cord, as much as 12 to 20% of the 26Al amounts present on day 20 postpartum remained in the tissues on day 730 postpartum. As the life span of rats is about 2 years, we conclude that considerable amounts of the 26Al taken up into the brain of suckling rats through maternal milk remained in their brain throughout their lifetime.

Transplacental passage of 26Al from pregnant rats to fetuses and 26Al transfer through maternal milk to suckling rats

Abstract Aluminium (Al) is toxic to the growth of fetuses and sucklings. However, the incorporation of Al into fetuses and sucklings in the periods of gestation and lactation has not been well clarified because Al lacks a suitable isotope for a tracer experiment. In this study, we used 26 Al (a radioisotope of Al with half-life of 716,000 yr) as a tracer, and measured 26 Al incorporation into fetuses and sucklings by accelerator mass spectrometry (AMS). To investigate Al incorporation into fetuses through transplacental passage, 26 Al ( 26 AlCl3) was subcutaneously injected into pregnant rats on day 15 of gestation. 26 Al was also subcutaneoulsy injected into lactating rats from day 1 to day 20 postpartum. By day 20 of gestation, 0.2% of the 26 Al injected into a pregnant rat had been transferred to the fetuses, and 26 Al was detected in the brain and liver of the fetuses. On day 9 postpartum, high levels of 26 Al were demonstrated in the brain, liver, kidneys and blood of suckling rats. It is concluded that 26 Al subcutaneously injected into pregnant rats and/or lactating rats is incorporated into their offspring through transplacental passage and/or maternal milk.

Creutzfeldt-Jakob disease with florid plaques after cadaveric dura mater graft.

A patient with dura‐associated Creutzfeldt‐Jakob disease (D‐CJD) which occurred about 15 years after a dura mater graft is reported in the present study. The prion protein gene analysis disclosed no mutation. The D‐CJD was atypical in: (i), the long interval between the onset of ataxia and the occurrence of dementia; (ii), the presence of transient myoclonus; and (iii), the presence of florid plaques in the brain. The electron‐microscopic findings showed bundles of amyloid filaments which radiated from the center of the plaques without degenerating neurites. This case of D‐CJD may belong to a new subtype of D‐CJD.

MICROPROBE PIXE ANALYSIS OF ALUMINIUM IN THE BRAINS OF PATIENTS WITH ALZHEIMER'S DISEASE

To investigate the cause of Alzheimers disease (senile dementia), we examined aluminium (Al) in the rat liver, and in the brains (hippocampus) of Alzheimers disease patients using heavy ion (5 MeV Si3+) microprobe and proton (2 MeV) microprobe PIXE analysis. Heavy ion microprobes (3 MeV Si2+) have several times higher sensitivity for Al detection than 2 MeV proton microprobes. (1) In the rat liver, Al was detected in the cell nuclei, where phosphorus (P) was most densely distributed. (2) We also demonstrated Al in the cell nuclei isolated from Alzheimers disease brains using heavy ion (5 MeV Si3+) microprobes. Al spectra were detected using 2 MeV proton microprobes in the isolated brain cell nuclei. Al could not be observed in areas where P was present in relatively small amounts, or was absent. Our results indicate that Alzheimers disease is caused by irreversible accumulation of Al in the nuclei of brain cells.

Aluminium toxicity in the rat liver and brain

Abstract To investigate the etiology of Alzheimers disease, we examined the brain and liver tissue uptake of aluminium 5–75 days after aluminium injection into healthy rats. Ten days after the last injection, Al was detected in the brain and the brain cell nuclei by particle-induced X-ray emission (PIXE) analysis. Al was also demonstrated in the liver and the liver cell nuclei by PIXE analysis and electron energy loss spectrometry (EELS). The morphological changes of the rat brain examined 75 days after the injection were similar to those which have been reportedly observed in the brain of patients with Alzheimers disease. These results support the theory that Alzheimers disease is caused by irreversible accumulation of aluminium in the brain, as well as in the nuclei of brain cells.

Aluminum Neurotoxicity and Alzheimer’s Disease

High aluminum concentrations have been demonstrated in the brains of patients with Alzheimer’s disease (senile dementia).1–4 Epidemiological studies have also reported that increased aluminum concentration in drinking water increases the incidence of Alzheimer’s disease.5 Based on these results, a theory that aluminum is the cause of Alzheimer’s disease has been postulated.1–5

Demonstration of Aluminum in the Brain of Patients with Alzheimer’s Disease

Epidemiological studies have revealed that increased aluminum (Al) concentration in drinking water increases the incidence of Alzheimer’s disease (senile dementia of Alzheimer’s disease type) (Martyn et al., 1989; Flaten, 1990; Neri and Hewitt, 1991). Al is a highly neurotoxic substance, and induces degeneration and death of nerve cells in the brains of humans and experimental animals (Mahurkar et al., 1973; Alfrey et al., 1976; Yumoto et al., 1992). We have reported that after subcutaneous injection of Al into rats, the numbers of dendrites and spines (postsynaptic structures of axodendritic synapses) of cortical nerve cells decreased markedly (Yumoto et al., 1992, 1993). These morphological changes were similar to those reported in the brains of patients with Alzheimer’s disease (Purpura, 1975).