Link between Aluminum and the Pathogenesis of Alzheimer's Disease: The Integration of the Aluminum and Amyloid Cascade Hypotheses

Abstract

Whilst being environmentally abundant, aluminum is not essential for life. On the contrary, aluminum is a widely recognized neurotoxin that inhibits more than 200 biologically important functions and causes various adverse effects in plants, animals, and humans. The relationship between aluminum exposure and neurodegenerative diseases, including dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii Peninsula and Guam, and Alzheimer's disease (AD) has been suggested. In particular, the link between aluminum and Alzheimer's disease has been the subject of scientific debate for several decades. However, the complex characteristics of aluminum bioavailability make it difficult to evaluate its toxicity and therefore, the relationship remains to be established. Mounting evidence has suggested that significance of oligomerization of β-amyloid protein and neurotoxicity in the molecular mechanism of AD pathogenesis. Aluminum may play crucial roles as a cross-linker in β-amyloid oligomerization. Here, we review the detailed characteristics of aluminum neurotoxicity based on our own studies and the recent literatures. Our aim is to revisit the link between aluminum and AD and to integrate aluminum and amyloid cascade hypotheses in the context of β-amyloid oligomerization and the interactions with other metals.

Figure 1

Effects of aluminum on the central nervous system. Major biological effects of Al on the central nervous system are depicted.

Figure 2

Cross-linking of protein by Al³⁺. Al³⁺ has a relatively small ionic radius (50 pm) with 3 positive charges; here it is compared to other metal ions such as Zn²⁺ (74 pm), Ca²⁺ (99 pm), and Na⁺ (95 pm). These characteristics enable Al to be an effective cross-linker of proteins.

Figure 3

Secretion of AβP from APP and its oligomerization. AβP is secreted by the cleavage of the APP N-terminus by β-secretase (BACE), followed by the intramembrane cleavage of the C-terminus by γ-secretase. APP also binds to Cu or Zn. Human AβP and rodent AβP differ by 3 amino acids (Arg⁵, Tyr¹⁰, and His¹³). AβP monomers form random-coil structures. However, under aging conditions or the existence of trace metals such as Al, Zn, and Cu, AβP self-aggregates and oligomerizes (dimmer to protofibrils), and then forms insoluble amyloid fibrils. Although monomeric AβPs are not toxic, oligomeric AβPs induce marked neuronal death.

Figure 4

Aggregation of AβP by Al and other metals. (A) Immunoblotting of AβP preincubated with Al and other metals. The solutions of AβP(1–40) were incubated at 37°C for 24 h with or without 1 mM of various metals, and were analyzed by SDS-PAGE and immunoblotting using an antibody to AβP. Each lane contained 4 μg AβP(1–40). Lane a: control, b: AlCl₃, c: ZnCl₂, d: CuCl₂, e: FeCl₃, f: CdCl₂, Modified from [134]. (B) Deposition of AβP on surfaces of cultured neurons. Solutions of AβP(1–40) preincubated at 37°C for 24 h (a), with 1 mM AlCl₃ (b), or 1 mM ZnCl₂ (c) were applied to cultured rat cortical neurons. After 2 days of exposure, cells were washed and double immunostained with a polyclonal antibody to AβP (green) and a monoclonal antibody to MAP2 (red), and observed by laser confocal microscope. Scale bar: 50 μm, modified from [64].

Figure 5

Modified aluminum hypothesis addressing the implications of Al and other trace metals in the pathogenesis of Alzheimer's disease. This model describes the implication of Al and other trace metals including Fe, Cu, and Zn in APP processing, generation and oligomerization of AβP, and the neurotoxic effects caused by AβP. Details are descried in the text.