The essential elements of Alzheimer's disease

Abstract

Treatments for Alzheimer's disease (AD) directed against the prominent amyloid plaque neuropathology are yet to be proved effective despite many phase 3 clinical trials. There are several other neurochemical abnormalities that occur in the AD brain that warrant renewed emphasis as potential therapeutic targets for this disease. Among those are the elementomic signatures of iron, copper, zinc, and selenium. Here, we review these essential elements of AD for their broad potential to contribute to Alzheimer's pathophysiology, and we also highlight more recent attempts to translate these findings into therapeutics. A reinspection of large bodies of discovery in the AD field, such as this, may inspire new thinking about pathogenesis and therapeutic targets.

Keywords: Alzheimer’s disease; PBT2; clioquinol; copper; ferroptosis; iron; selenium; zinc.

Figure 1

Neuronal zinc homeostasis is dysregulated in Alzheimer's disease. Zn²⁺ enters neuronal cytoplasm through ZIPs, whereas efflux from the cytoplasm is regulated by ZnTs. There are many types of ZIPs and ZnTs expressed in neurons, but ZnT3 is implicated in cognitive loss with aging and amyloid formation in AD. ZnT3 concentrates Zn²⁺ in glutamatergic synaptic vesicles that is released upon synaptic activity and then is normally rapidly taken up by unidentified energy-dependent mechanisms. During aging, mitochondrial energy is decreased, leading to more sluggish reuptake of extracellular Zn²⁺. Loss of estrogen, as occurs during menopause, increases ZnT3 protein levels, potentially increasing Zn²⁺ release. Extracellular Zn²⁺ binds to Aβ and induces its aggregation, becoming trapped in the amyloid. Intracellularly, metallothioneins, as the major Zn²⁺-buffering peptides, maintain free Zn²⁺ at appropriate levels, but neuronal Metallothionein III levels are depleted in AD. Increased cytoplasmic free Zn²⁺ enhances tau phosphorylation by activating CDK5, GSK3β, ERK1/2, or JNK kinases and by inhibiting PP2A activity. Aβ, amyloid β; APP, amyloid precursor protein; CDK5, cyclin-dependent kinase 5; ERK1/2, extracellular signal-regulated protein kinase 1/2; GSK3β, glycogen synthase kinase 3β; JNK, c-Jun N-terminal kinase; MTs, metallothioneins; NFTs, neurofibrillary tangles; PP2A, protein phosphatase 2A; ZIPs, zinc regulated transporter-like iron regulated transporter-like proteins; ZnTs, zinc transporter proteins.

Figure 2

Potential mechanisms of PBT2 in Alzheimer's disease. Soluble interstitial Aβ reacts with extracellular Zn²⁺ and Cu²⁺ to form protease-resistant Aβ oligomers and aggregates, which are in dissociable equilibrium with the soluble Aβ species. PBT2 reacts with accessible Zn²⁺ and Cu²⁺, promoting dissolution or uptake and degradation of the aggregates. PBT2 also dissociates Zn²⁺ and Cu²⁺ from being trapped by Aβ, neutralizing the charge of the metal ion and allowing it to passively move across cell membranes. This promotes the recycling of Zn²⁺ and Cu²⁺ from the cleft, normalizing functional fluxes, and intracellular metal pools. Aβ, amyloid β; APP, amyloid precursor protein; PBT2, 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol.

Figure 3

Copper dysregulation in Alzheimer's disease. Cu⁺ is taken up into neurons by CTR1 and exported by ATP7A/B. Aβ oligomers can trap extracellular Cu²⁺ and then embed into the membrane, forming a catalytic complex that generates H₂O₂. H₂O₂ is freely permeable and can migrate to deplete antioxidants like GSH and denature SOD1. In bulk tissue, copper levels are decreased, consistent with a decrease in the activity of ceruloplasmin. But the fraction of cytoplasmic-free Cu⁺ increases in AD-affected tissue, which might contribute to tau hyperphosphorylation by activation of CDK5 or GSK3β. Aβ, amyloid β; AD, Alzheimer's disease; APP, amyloid precursor protein; CDK5, cyclin-dependent kinase 5; GSH, glutathione; GSK3β, glycogen synthase kinase 3β; SOD1, superoxide dismutase 1.

Figure 4

AD-associated proteins and iron transport. In health, neuronal iron (Fe²⁺) export is regulated by tau-mediated APP trafficking. Tau guides the trafficking of APP cargo to the neuronal surface, where APP interacts with and stabilizes ferroportin, facilitating iron export from neurons. A reduction of soluble tau or FAD mutation of APP impairs iron export from neurons and results in iron retention. Similarly, when APP is cleaved by BACE1, ferroportin is not stabilized on the surface and does not function to export iron. The intracellular accumulation of Fe²⁺ increases the susceptibility to ferroptosis. AD, Alzheimer's disease; APP, amyloid precursor protein; BACE1, β-site amyloid precursor protein cleaving enzyme 1; FAD, familial AD.

Figure 5

Ferroptosis in Alzheimer's disease. In health, selenium (Se) in the brain can inhibit Aβ generation and tau hyperphosphorylation by modulating PP2A activity. Selenocysteine promotes the synthesis of GPx4, where it forms the active site. Accumulation of iron (e.g., from aging or from BACE1 processing of APP) increases the reaction of cytoplasmic Fe²⁺ with H₂O₂ to generate the hydroxyl radical (HO, Fenton chemistry), which then reacts with PUFA-containing membrane phospholipids, generating lipid peroxides and initiating lipid radical propagation, which then disrupts the plasma membrane and causes ferroptosis. This mechanism is initiated by autoxidation, but arachidonate lipoxygenase 15-mediated peroxidation of phospholipids can also initiate ferroptosis in an iron-dependent manner (374). Se, N-acetylcysteine (NAC), α-tocopherol (Vit E), and deferiprone act on different components of the pathway to prevent ferroptosis, potentially accounting for their putative clinical benefits for AD. AD, Alzheimer's disease; Aβ, amyloid β; APP, amyloid precursor protein; BACE1, β-site amyloid precursor protein cleaving enzyme 1; GPx4, glutathione peroxidase 4; PP2A, protein phosphatase 2A; PUFA, polyunsaturated fatty acids.