Brain aluminum in aging and Alzheimer disease

McDermott, Joseph; Smith, A. I.; Iqbal, Khalid; Wisniewski, H. M.

doi:10.1212/wnl.29.6.809

Cited by 259 publications

(100 citation statements)

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“…The controversy concerning levels of aluminum in AD brain is complicated by a lack of consensus concerning levels of aluminum in normal brain which are reported to vary by as much as 10-fold [24,25]. In the present work, cell lines were exposed to Fig.…”

Section: Discussionmentioning

confidence: 92%

Aluminum-induced oxidative events in cell lines: glioma are more responsive than neuroblastoma

Campbell

Prasad²,

Bondy

1999

Free Radical Biology and Medicine

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Abstract-Aluminum, a trivalent cation unable to undergo redox reactions, has been linked to many diseases such as dialysis dementia and microcytic anemia without iron deficiency. It has also been implicated in Alzheimer's disease although this is controversial. Because cell death due to oxidative injury is suspected to be a contributory factor in many neurological diseases and aluminum neurotoxicity, glioma (C-6) and neuroblastoma (NBP 2 ) cells were utilized to assess early changes in oxidative parameters consequent to a 48-h exposure to aluminum sulfate. A 500-M concentration of this salt produced a significant increase in reactive oxygen species (ROS) production and a significant decrease in glutathione (GSH) content in glioma cells. However, the same concentration of the aluminum salt did not lead to any significant changes in the neuroblastoma cells. Mitochondrial respiratory activity in glioma cells was also found to be significantly higher in the aluminum treated cells. As judged by morin-metal complex formation, aluminum can enter glioma cells much more readily than neuroblastoma cells. Thus, it is possible that the cerebral target following an acute exposure to aluminum may be glial rather than neuronal.

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Section: Discussionmentioning

confidence: 92%

Aluminum-induced oxidative events in cell lines: glioma are more responsive than neuroblastoma

Campbell

Prasad²,

Bondy

1999

Free Radical Biology and Medicine

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“…The third possibility may be that the acidic domain of APP binds to many metal ions and may form a bulky structure (Hesse et al, 1994) that may cause the translocational arrest. Many studies have implicated metal ions, including zinc, copper, iron, and aluminum, in the pathogenesis of AD (McDermott et al, 1979;Lovell et al, 1998;Zatta et al, 2003). Furthermore, some studies have also shown that the cellular concentrations of these metal ions were increased in AD brain (Basun et al, 1991;Loeffler et al, 1996;Jagannatha Rao et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain Is Associated with Mitochondrial Dysfunction

Devi¹,

Prabhu²,

Galati³

et al. 2006

J. Neurosci.

721

584

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Mitochondrial dysfunction is one of the major intracellular lesions of Alzheimer's disease (AD). However, the causative factors involved in the mitochondrial dysfunction in human AD are not well understood. Here we report that nonglycosylated full-length and C-terminal truncated amyloid precursor protein (APP) accumulates exclusively in the protein import channels of mitochondria of human AD brains but not in age-matched controls. Furthermore, in AD brains, mitochondrially associated APP formed stable ϳ480 kDa complexes with the translocase of the outer mitochondrial membrane 40 (TOM40) import channel and a super complex of ϳ620 kDa with both mitochondrial TOM40 and the translocase of the inner mitochondrial membrane 23 (TIM23) import channel TIM23 in an "N in mitochondria -C out cytoplasm " orientation. Accumulation of APP across mitochondrial import channels, which varied with the severity of AD, inhibited the entry of nuclearencoded cytochrome c oxidase subunits IV and Vb proteins, which was associated with decreased cytochrome c oxidase activity and increased levels of H 2 O 2 . Regional distribution of mitochondrial APP showed higher levels in AD-vulnerable brain regions, such as the frontal cortex, hippocampus, and amygdala. Mitochondrial accumulation of APP was also observed in the cholinergic, dopaminergic, GABAergic, and glutamatergic neuronal types in the category III AD brains. The levels of translocationally arrested mitochondrial APP directly correlated with mitochondrial dysfunction. Moreover, apolipoprotein genotype analysis revealed that AD subjects with the E3/E4 alleles had the highest content of mitochondrial APP. Collectively, these results suggest that abnormal accumulation of APP across mitochondrial import channels, causing mitochondrial dysfunction, is a hallmark of human AD pathology.

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“…Aluminum (Al) has been suggested to accelerate or play a causal role in the pathogenesis of AD. The metal is found in the brain of patients with this disorder [10, 39,541. However, other studies have been unable to confirm these findings [5,23,31 ]. [2,32,36,42].…”

Section: Introductionmentioning

confidence: 89%

Aluminum and copper interact in the promotion of oxidative but not inflammatory events: Implications for Alzheimer's disease

Becaria

Bondy

Campbell

2003

JAD

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Abstract. The etiology of Alzheimer's Disease (AD) is multifactorial. It has been suggested that transition metals such as copper (Cu) and iron (Fe) as well as aluminum (Al) may be involved in the pathogenesis of the disorder. While Cu and Fe are redox-active, Al only exists in the trivalent form and is redox-inert. We previously demonstrated that Al exposure causes an increase in inflammatory parameters in human glioblastoma T98G cells. In the present study we further demonstrate that co-exposure with Cu exacerbates the oxidative but not inflammatory effects of Al in this cell line. While Cu-induced reactive oxygen species (ROS) production was greatly enhanced in the presence of Al, TNF-a secretion induced by either metal was not further potentiated by simultaneous exposure to Al and Cu. Furthermore, exposure to both metals reduced the individual Al and Cu-induced activation of the immune-related transcription factor NF-,,,;B. Therefore, while synergistic interaction between the two metals increases oxidative events, this does not lead to potentiation of Al-induced inflammation. Thus the ability of aluminum to promote inflammatory processes does not depend on an increase ROS production induced by interaction with transition metals.

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Brain aluminum in aging and Alzheimer disease

Cited by 259 publications

References 0 publications

Aluminum-induced oxidative events in cell lines: glioma are more responsive than neuroblastoma

Aluminum-induced oxidative events in cell lines: glioma are more responsive than neuroblastoma

Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain Is Associated with Mitochondrial Dysfunction

Aluminum and copper interact in the promotion of oxidative but not inflammatory events: Implications for Alzheimer's disease

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