1.C.50 The Amyloid β-Protein Peptide (AβPP) Family
The AβP, associated with Alzheimer’s disease in humans, can be degraded to peptides, several of which can form oligomeric cation-selective peptide channels. For example, AβP-(25-35) and AβP-(1-40) form cation-selective channels; AβP-(1-42) forms slightly cation-selective channels, permeable to K+, Na+, Cl-, Mg2+ and Ca2+, and AβP-(25-35) forms voltage-dependent cation-selective channels (Kourie and Shorthouse, 2000). On the other hand, Bode et al. 2016 concluded that only Abeta(1-42), not Abeta(1-40), contains unique structural features that facilitate membrane insertion and channel formation, aligning ion channel formation with the differential neurotoxic effect of Abeta(1-40) and Abeta(1-42) in AD.
β-amyloid channels are formed dynamically (Jang et al., 2007). Truncated beta-amyloid peptide channels provide an alternative mechanism for Alzheimer's Disease and Down syndrome (Jang et al., 2010). Amyloid-beta membrane binding and permeabilization are distinct processes influenced separately by membrane charge and fluidity (Wong et al., 2009). Interestingly, the monomer of Ass1-42 activates type-1 insulin-like growth factor receptors and enhances glucose uptake in neurons and peripheral cells by promoting the translocation of the Glut3 glucose transporter from the cytosol to the plasma membrane (Giuffrida et al. 2015).
The mechanism of amyloid toxicity is poorly understood. There are two schools of thought: the first favors membrane destabilization by intermediate-to-large amyloid oligomers, with consequent thinning and non-specific ion leakage; the second favors ion-specific permeable channels lined by small amyloid oligomers. Published results currently support both mechanisms. However, the amyloid (Abeta) peptide has recently been shown to form a U-shaped 'beta-strand-turn-beta-strand' structure. This structure and the available physiological data present a challenge for computational biology--to provide candidate models consistent with the experimental data. Modeling based on small Abeta oligomers containing extramembranous N-termini predicts channels with shapes and dimensions consistent with experimentally derived channel structures (Zheng et al., 2008). These results support the hypothesis that small Abeta oligomers can form ion channels. For both the Aβ40 and Aβ42 peptides, the abundance of oligomers in the tetramer to 13-mer range contributed positively to both pore formation and cytotoxicity, while monomers, dimers, trimers, and the largest oligomers (>210 kDa) were negatively correlated to both phenomena (Prangkio et al. 2012).
Emerging evidence supports the ion channel mechanism for Alzheimer's disease pathophysiology wherein small β-amyloid (Aβ) oligomers insert into the cell membrane, forming toxic ion channels and destabilizing the cellular ionic homeostasis. Amyloid oligomers consist of double-layered β-sheets where each monomer folds into β-strand-turn-β-strand, and the monomers are stacked atop each other, forming β-barrel channels. The subunits appear mobile, allowing unregulated, hence toxic, ion flux (Jang et al., 2010).
In Alzheimer's disease, calcium permeability through cellular membranes appears to underlie neuronal cell death, and calcium permeability involves toxic ion channels. Jang et al., (2009) modeled Alzheimer's disease ion channels of different sizes (12-mer to 36-mer) in the lipid bilayer using molecular dynamics simulations. Abeta channels consist of a U-shaped beta-strand-turn-beta-strand motif. Beta-sheet channels break into loosely associated mobile beta-sheet subunits. The preferred channel sizes are made of 16- to 24-mer subunits. Mobile subunits were also observed for beta-sheet channels formed by cytolytic PG-1 beta-hairpins (1.C.33.1.9). Toxic ion channels formed by beta-sheets spontaneously break into loosely interacting dynamic units that associate and dissociate leading to toxic ionic fluxes.
Secretases generate amyloid β-peptides which cause Alzheimer's disease (Steiner et al., 2006). The α-secretase complex, consisting of four proteins, catalyzes intramembranous proteolysis. The complex is a spherical transmembrane particle with an interior chamber that accommodates its catalytic residues and the substrate protein. Two potential exit sites have been visualized by electron microscopy (Steiner et al., 2006). Homodimerization of the peptide, C99, protects it from cleavage within the transmembrane helix by gamma-secretase (Winkler et al. 2015).
.Alzheimer's disease (AD) associated peptide, amyloid beta (Abeta), may have the potential to non-specifically solubilize or permeabilize membranes, and it exhibits detergent and pore-forming properties. Damage to the membrane or integrity of synaptic vesicles could compromise their functions. The intact synaptic vesicle could be a direct site of attack by Abeta(1-42) (Aβ42) in AD pathology, but Allen & Chiu (2008) could not provide evidence for this postulate. The amyloid precursor protein has a flexible TMS and binds cholesterol (Barrett et al. 2012). Aβ40 aggregates into amyloid fibrils, whereas Aβ42 assembles into oligomers that insert into lipid bilayers, β-barrel pore-forming Aβ42 oligomers (βPFOsAβ42) (Serra-Batiste et al. 2016). Aβ42 has a more prominent role in AD than Aβ40, the higher propensity of Aβ42 to form βPFOs may explain this difference in AD.
Protein MLP1 of S. cerevisiae (1875aas; TC #9.A.14.1.1) is similar in sequence to AD amyloid beta in the region 348-608 in the latter and 1459-1680 in the former (e-5).
The transport reaction is:
ions (in) ions (out).