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).

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).

The transport reaction is:

ions (in) ions (out).



This family belongs to the Beta-Amyloid Protein-Protease Inhibitor Superfamily.

 

References:

Abd-Elrahman, K.S., A. Albaker, J.M. de Souza, F.M. Ribeiro, M.G. Schlossmacher, M. Tiberi, A. Hamilton, and S.S.G. Ferguson. (2020). Aβ oligomers induce pathophysiological mGluR5 signaling in Alzheimer's disease model mice in a sex-selective manner. Sci Signal 13:.

Allen, P.B., and D.T. Chiu. (2008). Alzheimer's disease protein Abeta(1-42) does not disrupt isolated synaptic vesicles. Biochim. Biophys. Acta. 1782: 326-334.

Arispe, N. (2004). Architecture of the Alzheimer's A beta P ion channel pore. J. Membr. Biol. 197: 33-48.

Barrett, P.J., Y. Song, W.D. Van Horn, E.J. Hustedt, J.M. Schafer, A. Hadziselimovic, A.J. Beel, and C.R. Sanders. (2012). The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science 336: 1168-1171.

Bode, D.C., M.D. Baker, and J.H. Viles. (2016). Ion Channel Formation by Amyloid-β42 Oligomers but not Amyloid-β40 in Cellular Membranes. J. Biol. Chem. [Epub: Ahead of Print]

Canu, N., I. Pagano, L.R. La Rosa, M. Pellegrino, M.T. Ciotti, D. Mercanti, F. Moretti, V. Sposato, V. Triaca, C. Petrella, I.N. Maruyama, A. Levi, and P. Calissano. (2017). Association of TrkA and APP Is Promoted by NGF and Reduced by Cell Death-Promoting Agents. Front Mol Neurosci 10: 15.

Demuro, A., M. Smith, and I. Parker. (2011). Single-channel Ca2+ imaging implicates Aβ1-42 amyloid pores in Alzheimer's disease pathology. J. Cell Biol. 195: 515-524.

Di Scala C., Chahinian H., Yahi N., Garmy N. and Fantini J. (2014). Interaction of Alzheimer's beta-amyloid peptides with cholesterol: mechanistic insights into amyloid pore formation. Biochemistry. 53(28):4489-502.

Giuffrida, M.L., M.F. Tomasello, G. Pandini, F. Caraci, G. Battaglia, C. Busceti, P. Di Pietro, G. Pappalardo, F. Attanasio, S. Chiechio, S. Bagnoli, B. Nacmias, S. Sorbi, R. Vigneri, E. Rizzarelli, F. Nicoletti, and A. Copani. (2015). Monomeric ß-amyloid interacts with type-1 insulin-like growth factor receptors to provide energy supply to neurons. Front Cell Neurosci 9: 297.

Hassan, M., S. Shahzadi, H. Raza, M.A. Abbasi, H. Alashwal, N. Zaki, A.A. Moustafa, and S.Y. Seo. (2019). Computational investigation of mechanistic insights of Aβ42 interactions against extracellular domain of nAChRα7 in Alzheimer''s disease. Int J. Neurosci. 129: 666-680.

Jang, H., F.T. Arce, S. Ramachandran, R. Capone, R. Azimova, B.L. Kagan, R. Nussinov, and R. Lal. (2010). Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer's Disease and Down syndrome. Proc. Natl. Acad. Sci. USA 107: 6538-6543.

Jang, H., J. Zheng, and R. Nussinov. (2007). Models of β-amyloid ion channels in the membrane suggest that channel formation in the bilayer is a dynamic process. Biophys. J. 93: 1938-1949.

Kim, M., J. Son, and Y. Kim. (2021). NMR Studies of the Ion Channel-Forming Human Amyloid-β with Zinc Ion Concentrations. Membranes (Basel) 11:.

Korte, M. (2019). Neuron.al function of Alzheimer''s protein. Science 363: 123-124.

Kourie, J.I. and A.A. Shorthouse (2000). Properties of cytotoxic peptide-formed ion channels. Am. J. Physiol. Cell Physiol. 278: C1063-C1087.

Liu, T., T. Zhang, M. Nicolas, L. Boussicault, H. Rice, A. Soldano, A. Claeys, I. Petrova, L. Fradkin, B. De Strooper, M.C. Potier, and B.A. Hassan. (2021). The amyloid precursor protein is a conserved Wnt receptor. Elife 10:.

Manville, R.W. and G.W. Abbott. (2021). The Amyloid Precursor Protein C99 Fragment Modulates Voltage-Gated Potassium Channels. Cell Physiol Biochem 55: 157-170.

Matsuzaki, K. (2022). Elucidation of Complex Dynamic Intermolecular Interactions in Membranes. Chem Pharm Bull (Tokyo) 70: 1-9.

Maulik, M., L. Vasan, A. Bose, S. Dutta Chowdhury, N. Sengupta, and J. Das Sarma. (2020). Amyloid-β regulates gap junction protein connexin 43 trafficking in cultured primary astrocytes. J. Biol. Chem. 295: 15097-15111.

Ngo, S.T., P. Derreumaux, and V.V. Vu. (2019). Probable Transmembrane Amyloid α-Helix Bundles Capable of Conducting Ca Ions. J Phys Chem B 123: 2645-2653.

Prangkio, P., E.C. Yusko, D. Sept, J. Yang, and M. Mayer. (2012). Multivariate Analyses of Amyloid-Beta Oligomer Populations Indicate a Connection between Pore Formation and Cytotoxicity. PLoS One 7: e47261.

Remnestål, J., S. Bergström, J. Olofsson, E. Sjöstedt, M. Uhlén, K. Blennow, H. Zetterberg, A. Zettergren, S. Kern, I. Skoog, P. Nilsson, and A. Månberg. (2021). Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds. Alzheimers Res Ther 13: 54.

Serra-Batiste, M., M. Ninot-Pedrosa, M. Bayoumi, M. Gairí, G. Maglia, and N. Carulla. (2016). Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments. Proc. Natl. Acad. Sci. USA 113: 10866-10871.

Steiner, H., M. Than, W. Bode, and C. Haass. (2006). Pore-forming scissors? A first structural glimpse of γ-secretase. Trends Biochem. Sci. 31: 491-493.

Strodel, B., J.W. Lee, C.S. Whittleston, and D.J. Wales. (2010). Transmembrane structures for Alzheimer's Aβ(1-42) oligomers. J. Am. Chem. Soc. 132: 13300-13312.

Venko, K., M. Novič, V. Stoka, and E. Žerovnik. (2021). Prediction of Transmembrane Regions, Cholesterol, and Ganglioside Binding Sites in Amyloid-Forming Proteins Indicate Potential for Amyloid Pore Formation. Front Mol Neurosci 14: 619496.

Winkler E., Julius A., Steiner H. and Langosch D. (2015). Homodimerization Protects the Amyloid Precursor Protein C99 Fragment from Cleavage by gamma-Secretase. Biochemistry. 54(40):6149-52.

Wong, P.T., J.A. Schauerte, K.C. Wisser, H. Ding, E.L. Lee, D.G. Steel, and A. Gafni. (2009). Amyloid-beta membrane binding and permeabilization are distinct processes influenced separately by membrane charge and fluidity. J. Mol. Biol. 386: 81-96.

Zheng, J., H. Jang, and R. Nussinov. (2008). Beta2-microglobulin amyloid fragment organization and morphology and its comparison to Abeta suggests that amyloid aggregation pathways are sequence specific. Biochemistry 47: 2497-2509.

Zhu, F., W. Wang, F. Zhang, M.K. Dhinakaran, Y. Wang, R. Wang, J. Cheng, M.E. Toimil-Molares, C. Trautmann, and H. Li. (2020). Selective transmembrane transport of Aβ protein regulated by tryptophan enantiomers. Chem Commun (Camb). [Epub: Ahead of Print]

Examples:

TC#NameOrganismal TypeExample
1.C.50.1.1

Alzheimer''s disease (AD) amyloid β-protein (amino acids 1-42) (Abeta protein or AβP or Aβ42).  Aβ pores may consist of tetrameric and hexameric beta-sheet subunits (Strodel et al. 2010).  Residues 22 - 35 in the peptide binds cholesterol to form Ca2+-permeable pores (Di Scala et al. 2014).  Cholesterol promotes the insertion of Abeta in the plasma membrane, induces alpha-helical structure formation, and forces the peptide to adopt a tilted topology that favours oligomerization. Bexarotene, an amphipathic drug for the treatment of neurodegenerative diseases, competes with cholesterol for binding to Abeta and prevents oligomeric channel formation (Di Scala et al. 2014). The beta-amyloid protein is involved in the activation of the nAChRalpha7 receptor (Hassan et al. 2019). Tryptophan enantiomers (d/l-Trp) introduced into artificial nanochannels regulate the chiral selective transport of Abeta proteins; the l-Trp channel shows selectivity for the transport of Abeta protein (Zhu et al. 2020). The prevalence, presentation, and progression of Alzheimer's disease (AD) differ between men and women, although β-amyloid (Aβ) deposition is a pathological hallmark of AD in both sexes. Aβ-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, mGluR5 exhibits distinct sex-dependent profiles (Abd-Elrahman et al. 2020). mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aβ oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aβ-mGluR5 interaction is not depend on estrogen, but rather Aβ interaction with cellular prion protein (PrPC), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aβ oligomers, and PrPC was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated Aβ pathology, and reversed cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female counterparts. Aβ oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. mGluR5 does not contribute to Aβ pathology in females, highlighting the complexity of mGluR5 pharmacology and Aβ signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics (Abd-Elrahman et al. 2020). Proteins associated with or anchored to the plasma membrane are associated with cerebrospinal fluid biomarkers of amyloid and tau pathology in AD (Remnestål et al. 2021). The architecture of the Alzheimer's A beta P ion channel pore has been determined (Arispe 2004). A transmembrane annular polymeric structure may be responsible for the ion channel properties of the membrane-bound A beta P (Arispe 2004). Arispe 2004 synthesized peptides that encompass the histidine dyad (H-H) hypothesized to line the pore and showed that peptides designed to most closely match the proposed pore are the most effective at blocking ion currents through the membrane-incorporated A beta P channel. Abeta) proteins can form ion pores in the cell membrane, and the structure of the transmembrane domain of Abeta ion channels is known. Substances that block or inhibit the formation of Abeta ion channels are known, and zinc ions are considered as potential inhibitors of AD (Kim et al. 2021).

Animals

AβP of Rattus norvegicus

 
1.C.50.1.2

The Alzheimer’s disease amyloid precursor β-protein (Aβpeptide; precursor: App, γ-secretase) (42aas) (3-d structure is known from NMR spectroscopy (1Z0Q_A; Jang et al., 2007; Zheng et al., 2008)).  This peptide is derived from the amyloid βA4 protein isoform f (NP_001129602)) which forms variable oligomeric toxic pores leading to cytosolic calcium elevation and Alzheimer's disease (Demuro et al., 2011). The monomer of Ass1-42 normally 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). At nanomolar concentrations, APPsα is an allosteric activator of α7-nAcChR (see TC family 1.A.9), mediated by the C-terminal 16 aas (CTα16) (Korte 2019). The amyloid precursor protein is a conserved Wnt receptor (Liu et al. 2021).

Animals

Aβ-peptide from the amyloid βA4 protein isoform f of Homo sapiens (NP_001129602)

 
1.C.50.1.3

Beta amyloid protein-like, isoform D of 888 aas

Animals


Beta amyloid protein-like, isoform D  of Drosophila melanogaster
 
1.C.50.1.4

Amyloid protein 1 of 629 aas

Animals

Amyloid protein 1 of Hydra vulgaris (Hydra) (Hydra attenuata)