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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.  Aβ peptide oligomers may be able to form transmembrane α-helix bundles that provide feasible pathways for Ca2+ transport (Ngo et al. 2019). In fact, any amyloid-forming protein may have the potential to form pores. Oligomerization and the alpha-TM helix to beta-TM strands transition on lipid rafts seem to be the common key events (Venko et al. 2021). The amyloid precursor protein C99 fragment modulates voltage-gated potassium channels (Manville and Abbott 2021). 

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). Amyloid-beta also regulates connexin 43 (TC# 1.A.24.1.1) trafficking in cultured primary astrocytes (Maulik et al. 2020). How lipids and their inhomogeneous distributions regulate the structures and functions of antimicrobial peptides as well as Alzheimer's amyloid beta-protein, and how TMS-TMS and membrane protein-protein interactions are modulated by lipids have been discussed (Matsuzaki 2022). The structure of tyrosine-10 favors ionic conductance of Alzheimer's disease-associated full-length amyloid-β channels (Karkisaval et al. 2024).

Two schools of thought explain amyloid toxicity: 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 been shown to form a U-shaped 'beta-strand-turn-beta-strand' structure. 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), supporting the hypothesis that small Abeta oligomers form ion channels.  For both the Aβ40 and Aβ42 peptides, the abundance of oligomers in the tetramer to 13-mer range contributes 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).

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 is favored. 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). Amyloid precursor protein (APP) associates with tropomyosin receptor kinase A (TrkA) via their transmembrane regions, and this association is regulated by cell death-promoting agents (Canu et al. 2017).

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.

Toxic amyloid beta oligomers (AbetaOs) accumulate in Alzheimer's disease (AD) and in animal models of AD. Their structures are heterogeneous, and they are found in both intracellular and extracellular sites. When given to CNS cultures or injected ICV into primates, AbetaOs cause impaired synaptic plasticity, loss of memory, tau hyperphosphorylation and tangle formation, synapse elimination, oxidative and ER stress, inflammatory microglial activation, and selective nerve cell death. Memory loss and pathology in transgenic models are prevented by AbetaO antibodies, while Aducanumab, an antibody that targets AbetaOs as well as fibrillar Abeta, has provided cognitive benefit to humans in early clinical trials (DiChiara et al. 2017). AbetaOs are widely thought to be the major toxic form of Abeta. Findings are consistent with the hypothesis that AbetaOs act as neurotoxins because they attach to particular membrane protein docks containing Na/K ATPase-alpha3, where they inhibit ATPase activity and pathologically restructure dock composition and topology in a manner leading to excessive Ca++ build-up (DiChiara et al. 2017).

Amphipathic peptides can cause biological membranes to leak either by dissolving their lipid content via a detergent-like mechanism or by forming pores on the membrane surface. These modes of membrane damage have been related to the toxicity of amyloid peptides and to the activity of antimicrobial peptides. Yang et al. 2022 performed tan all-atom simulations in which membrane-bound amphipathic peptides self-assemble into beta-sheets that subsequently either form stable pores inside the bilayer or drag lipids out of the membrane surface. An analysis of these simulations showed that the acyl tails of lipids interact strongly with non-polar side chains of peptides deposited on the membrane. These strong interactions enable lipids to be dragged out of the bilayer by oligomeric structures accounting for detergent-like damage. They also disturb the orientation of lipid tails in the vicinity of peptides. These distortions are minimized around pore structures. Membrane-bound beta-sheets become twisted with one of their extremities partially penetrating the lipid bilayer. This allows peptides on opposite leaflets to interact and form a long transmembrane beta-sheet that initiates poration. In simulations, where peptides are deposited on a single leaflet, the twist in beta-sheets allows them to penetrate the membrane and form pores (Yang et al. 2022).

The transport reaction is:

ions (in) ions (out).

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