AD is the most common neurodegenerative disease; currently affecting about 24 million people worldwide.1-6,12-16 Unlike the other major causes of death in the United States, such as heart disease and cancer, the numbers affected by AD are projected to increase with extrapolated values reaching around 100 million by 2050.1-6,12-16 This can be attributed to the absence of therapeutic agents with current FDA- approved drugs only offering symptomatic relief through control of the level and activity of neurotransmitters (e.g., donepezil and memantine related to acetylcholine and glutamate, respectively).1,2,6 Unfortunately, these treatments are only beneficial for short periods of time (6 to 12 months), thus
stressing the urgent need for the new discovery of effective treatment options.1,2,6 In order to achieve these future breakthroughs in drug discovery, an advance in the current understanding of the complex disease etiology is critical.
Figure 1.1. A schematic representation of the amyloid cascade hypothesis and the metal ion hypothesis.
The processing of the amyloid precursor protein (APP) by β- and γ-secretases [green segment: the respective soluble N-terminal cleavage products, sAPPα and sAPPβ; red segment: amyloidogenic isoforms, Aβ40 and Aβ42; blue segment: the APP intracellular domain (AICD)] leads to the production of Aβ40 and Aβ42 monomers that can go through a slow nucleation stage followed by a fast elongation phase resulting in the formation of mature aggregated fibrils. The overproduction of Aβ aggregates and the ineffective clearance cause Aβ plaque deposition. Metal interaction with Aβ species can facilitate peptide aggregation pathways, stabilize toxic conformations, and generate the production of reactive oxygen species (ROS) through Fenton-like reactions.
Histopathologically, the AD-afflicted brain is characterized by the presence of senile plaques and neurofibrillary tangles (NFTs) composed of misfolded, aggregated amyloid-β (Aβ) peptides and hyperphosphorylated tau protein (ptau), respectively, both being considered hallmarks of the disease
(Figure 1.1).2-6,12-21 The distinct nature of Aβ plaques and NFTs has initially made them prime suspects as the toxic, causative agents of AD leading to the broad acceptance of their respective hypotheses (i.e., amyloid cascade and tau hypotheses).2-6,12-16 The amyloid cascade hypothesis claims that the overproduction and/or ineffective clearance of Aβ, the proteolytic cleavage product of the amyloid precursor protein (APP) by β- and γ-secretases, result in the accumulation of Aβ, which tends to aggregate into toxic oligomeric species (Figure 1.1).2-6,12-17 Initial evidence supporting the amyloid cascade hypothesis has been largely supplied from the less common, familial form of the disease (i.e., ca.
5% of all AD cases are considered to be familial) that often occurs earlier in life (45 years of age or younger) where genetic mutations in the APP, presenilin 1 (PS1) and presenilin 2 (PS2), parts of the excision machinery that composes γ-secretase, have been identified.2-6,12-16,18-21
Mutations in these genes can lead to various phenotypes, such as the enhanced production of APP and Aβ, and the generation of the more aggregation-prone isoform, Aβ42.2-6 Carriers of these specific alleles are almost certain to be affected by the disease. How the genetic component translates to the more common sporadic form of the disease as well as a mechanistic understanding of how altered APP processing or Aβ production engenders toxicity, has not been fully elucidated. Although multiple hypotheses, such as inducing lipid peroxidation, impairing synapse plasticity, and disrupting membrane potentials, through the formation of pores have been proposed.5,6,12-17
The aggregation and accumulation of Aβ may not be the only factor contributing to neuronal toxicity.
The unfortunate lack of clinically successful compounds targeted at either preventing or reversing the aggregation pathways of Aβ, as well as the poor correlation between plaque load and neuronal function (i.e., 20–40% of cognitively normal individuals have plaque loads consistent with AD) have spurred researchers to consider additional parameters and look in different locations for new, potential contributors to AD pathogenesis.5,6 The involvement of metal ions in AD has been evident upon the closer analysis of senile plaques where elevated levels of metals [i.e., Cu(I/II), Zn(II), Fe(II/III)] are found to be co-localized.3,5,13-16,17,22,23
Aβ has been shown mainly through in vitro investigations to coordinate to these metal ions.2,5,13,16,17,23
The dyshomeostasis and miscompartmentalization of metals in the AD-affected brain consummated the metal ion hypothesis that attributes misregulated metals as a causative feature in the initiation and progression of the disease.2-6,13,15-17,23
Metal ions are indicated to facilitate Aβ aggregation and stabilize specific, toxic conformations of the peptides (Figure 1.1).5,13,23,24 Furthermore, redox active metal ions can induce the overproduction of reactive oxygen species (ROS) through Fenton- like reactions with and without Aβ, which can cause detrimental damage of biological molecules eventually leading to neuronal death (i.e., oxidative stress hypothesis; Figure 1.2).5,13,16,17,23
Figure 1.2. The oxidative stress hypothesis. The ROS generated from labile metal pools and redox active metal bound to Aβ can engender damage of DNA, lipids, and proteins, as well as induce mitochondrial dysfunction, all of which can contribute to neuronal death.
Different from Aβ which forms aggregates early in the disease pathway and whose plaques are poorly correlated with neuronal impairment, the generation of NFTs composed of tau aggregates occurs much closer to the appearance of clinical symptoms with a more significant connection to neuronal loss.6,13 Tau, along with other microtubule-associated proteins (MAPs), are essential for the structural stability and integrity of the intrinsically dynamic microtubules (MTs).4,6,12,13,18,19
The stabilization of MTs by tau is associated with normal anterograde and retrograde shuttling of essential nutrients, neurotransmitters, and organelles.6,12,13 Therefore, when hyperphosphorylation of tau catalyzes its release from MTs, toxicity arises via either the creation of aggregates affording paired helical filaments (PHFs) and eventually NFTs, or impaired synaptic plasticity and axonal transport processes that could be disturbed upon loss and aggregation of tau and other MAPs (Figure 1.3).6,12,13 Overall, Aβ, tau, metal ions, and oxidative stress are only a part of other possible factors that could lead to AD; however, the interconnection between these facets has suggested potential avenues and mechanisms toward neuronal death and AD, thus highlighting the extremely complex nature of the disease.13,25