Anti-amyloid β hydrophobic peptides in Alzheimer’s disease: biomarkers and therapeutic potential

Abstract

Intracellular amyloid β oligomers (AβOs) have been linked to Alzheimer’s disease (AD) pathogenesis and to the neuronal damage in this neurodegenerative disease. Calmodulin, which binds AβO with very high affinity, plays a pivotal role in Aβ-induced neurotoxicity and has been used as a model template protein for the design of AβO-antagonist peptides. The hydrophobic amino acid residues of the COOH-terminus domain of Aβ play a leading role in its interaction with the intracellular proteins that bind AβO with high affinity. This review focuses on Aβ-antagonist hydrophobic peptides that bind to the COOH-terminus of Aβ and their endogenous production in the brain, highlighting the role of the proteasome as a major source of this type of peptides. It is emphasized that the level of these hydrophobic endogenous neuropeptides undergoes significant changes in the brain of AD patients relative to age-matched healthy individuals. It is concluded that these neuropeptides may become helpful biomarkers for the evaluation of the risk of the onset of sporadic AD and/or for the prognosis of AD. In addition, Aβ-antagonist hydrophobic peptides that bind to the COOH-terminus of Aβ seem a priori good candidates for the development of novel AD therapies, which could be used in combination with other drug-based therapies. Future perspectives and limitations for their use in the clinical management of AD are briefly discussed.

Keywords

Amyloid β / Alzheimer’s disease / hydrophobic peptides / proteasome / endogenous neuropeptides / biomarkers / therapy

References

[1] Gauthier S,Webster C,Servaes S,Morais JA,Rosa-Neto P.World Alzheimer Report 2022: Life after diagnosis: Navigating treatment, care and support [Internet]London: Alzheimer’s Disease International; c2022 [cited 2024 Dec 26]. Available from: https://www.alzint.org/u/World-Alzheimer-Report-2022.pdf

[2] Braak H,de Vos RA,Jansen EN,Bratzke H,Braak E.Chapter 20 Neuropathological hallmarks of Alzheimer’s and Parkinson’s diseases.Prog Brain Res.1998;117:267-85.

[3] Chen GF,Xu TH,Yan Y,Zhou YR,Jiang Y,Melcher K,et al.Amyloid beta: structure, biology and structure-based therapeutic development.Acta Pharmacol Sin.2017;38:1205-35.

[4] Mirza Z,Pillai VG,Kamal MA.Protein interactions between the C-terminus of Aβ-peptide and phospholipase A₂ - a structure biology based approach to identify novel Alzheimer’s therapeutics.CNS Neurol Disord Drug Targets.2014;13:1224-31.

[5] Guo JP,Arai T,Miklossy J,McGeer PL.Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease.Proc Natl Acad Sci U S A.2006;103:1953-8.

[6] Luan K,Rosales JL,Lee KY.Viewpoint: Crosstalks between neurofibrillary tangles and amyloid plaque formation.Ageing Res Rev.2013;12:174-81.

[7] Younkin SG.The role of Aβ42 in Alzheimer’s disease.J Physiol Paris.1998;92:289-92.

[8] Sun X,Chen WD,Wang YD.β-Amyloid: the key peptide in the pathogenesis of Alzheimer’s disease.Front Pharmacol.2015;6:221.

[9] Sathya M,Premkumar P,Karthick C,Moorthi P,Jayachandran KS,Anusuyadevi M.BACE1 in Alzheimer’s disease.Clin Chim Acta.2012;414:171-8.

[10] Silvestri L,Camaschella C.A potential pathogenetic role of iron in Alzheimer’s disease.J Cell Mol Med.2008;12:1548-50.

[11] Peters DG,Connor JR,Meadowcroft MD.The relationship between iron dyshomeostasis and amyloidogenesis in Alzheimer’s disease: Two sides of the same coin.Neurobiol Dis.2015;81:49-65.

[12] Wang F,Wang J,Shen Y,Li H,Rausch WD,Huang X.Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?Front Aging Neurosci.2022;14:830569.

[13] Khan A,Dobson JP,Exley C.Redox cycling of iron by Aβ₄₂.Free Radic Biol Med.2006;40:557-69.

[14] Cheignon C,Tomas M,Bonnefont-Rousselot D,Faller P,Hureau C,Collin F.Oxidative stress and the amyloid beta peptide in Alzheimer’s disease.Redox Biol.2018;14:450-64.

[15] Chew H,Solomon VA,Fonteh AN.Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies.Front Physiol.2020;11:598.

[16] Solomon A,Kivipelto M,Wolozin B,Zhou J,Whitmer RA.Midlife serum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later.Dement Geriatr Cogn Disord.2009;28:75-80.

[17] Loera-Valencia R,Goikolea J,Parrado-Fernandez C,Merino-Serrais P,Maioli S.Alterations in cholesterol metabolism as a risk factor for developing Alzheimer's disease: Potential novel targets for treatment.J Steroid Biochem Mol Biol.2019;190:104-14.

[18] Grösgen S,Grimm MO,Friess P,Hartmann T.Role of amyloid beta in lipid homeostasis.Biochim Biophys Acta.2010;1801:966-74.

[19] Zhang X,Zhou K,Wang R,Cui J,Lipton SA,Liao FF,et al.Hypoxia-inducible Factor 1α (HIF-1α)-mediated Hypoxia Increases BACE1 Expression and β-Amyloid Generation.J Biol Chem.2007;282:10873-80.

[20] Rottkamp CA,Raina AK,Zhu X,Gaier E,Bush AI,Atwood CS,et al.Redox-active iron mediates amyloid-β toxicity.Free Radic Biol Med.2001;30:447-50.

[21] Bazzari FH,Bazzari AH.BACE1 Inhibitors for Alzheimer’s Disease: The Past, Present and Any Future?Molecules.2022;27:8823.

[22] Ramakrishna K,Karuturi P,Siakabinga Q,T.A G,Krishnamurthy S,Singh S,et al.A G, Krishnamurthy S, Singh S, et al. Indole-3 Carbinol and Diindolylmethane Mitigated β-Amyloid-Induced Neurotoxicity and Acetylcholinesterase Enzyme Activity: In Silico, In Vitro, and Network Pharmacology Study.Diseases.2024;12:184.

[23] Ramakrishna K,Nalla LV,Naresh D,Venkateswarlu K,Viswanadh MK,Nalluri BN,et al.WNT-β Catenin Signaling as a Potential Therapeutic Target for Neurodegenerative Diseases: Current Status and Future Perspective.Diseases.2023;11:89.

[24] Millucci L,Ghezzi L,Bernardini G,Santucci A.Conformations and biological activities of amyloid beta peptide 25-35.Curr Protein Pept Sci.2010;11:54-67.

[25] Knobloch M,Konietzko U,Krebs DC,Nitsch RM.Intracellular Aβ and cognitive deficits precede β-amyloid deposition in transgenic arcAβ mice.Neurobiol Aging.2007;28:1297-306.

[26] Oakley H,Cole SL,Logan S,Maus E,Shao P,Craft J,et al.Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer’s Disease Mutations: Potential Factors in Amyloid Plaque Formation.J Neurosci.2006;26:10129-40.

[27] Billings LM,Oddo S,Green KN,McGaugh JL,LaFerla FM.Intraneuronal Aβ Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice.Neuron.2005;45:675-88.

[28] Jin S,Kedia N,Illes-Toth E,Haralampiev I,Prisner S,Herrmann A,et al.Amyloid-β(1-42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity.J Biol Chem.2016;291:19590-606.

[29] Hu X,Crick SL,Bu G,Frieden C,Pappu RV,Lee JM.Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide.Proc Natl Acad Sci U S A.2009;106:20324-9.

[30] Karlawish J,Grill JD.The approval of Aduhelm risks eroding public trust in Alzheimer research and the FDA.Nat Rev Neurol.2021;17:523-4.

[31] Lai AY,McLaurin J.Mechanisms of amyloid-Beta Peptide uptake by neurons: the role of lipid rafts and lipid raft-associated proteins.Int J Alzheimers Dis.2010;2011:548380.

[32] Potter H,Wisniewski T.Apolipoprotein e: essential catalyst of the Alzheimer amyloid cascade.Int J Alzheimers Dis.2012;2012:489428.

[33] Kawarabayashi T,Shoji M,Younkin LH,Wen-Lang L,Dickson DW,Murakami T,et al.Dimeric Amyloid β Protein Rapidly Accumulates in Lipid Rafts followed by Apolipoprotein E and Phosphorylated Tau Accumulation in the Tg2576 Mouse Model of Alzheimer’s Disease.J Neurosci.2004;24:3801-9.

[34] Wisniewski T,Frangione B.Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid.Neurosci Lett.1992;135:235-8.

[35] Huynh TV,Davis AA,Ulrich JD,Holtzman DM.Apolipoprotein E and Alzheimer’s disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins.J Lipid Res.2017;58:824-36.

[36] Frost GR,Li YM.The role of astrocytes in amyloid production and Alzheimer’s disease.Open Biol.2017;7:170228.

[37] Liang Y,Raven F,Ward JF,Zhen S,Zhang S,Sun H,et al.Upregulation of Alzheimer’s Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo.J Alzheimers Dis.2020;76:1071-82.

[38] Poejo J,Salazar J,Mata AM,Gutierrez-Merino C.Binding of Amyloid β(1–42)-Calmodulin Complexes to Plasma Membrane Lipid Rafts in Cerebellar Granule Neurons Alters Resting Cytosolic Calcium Homeostasis.Int J Mol Sci.2021;22:1984.

[39] Poejo J,Orantos-Aguilera Y,Martin-Romero FJ,Mata AM,Gutierrez-Merino C.Internalized Amyloid-β (1-42) Peptide Inhibits the Store-Operated Calcium Entry in HT-22 Cells.Int J Mol Sci.2022;23:12678.

[40] Kandimalla KK,Scott OG,Fulzele S,Davidson MW,Poduslo JF.Mechanism of Neuronal versus Endothelial Cell Uptake of Alzheimer’s Disease Amyloid β Protein.PLoS One.2009;4:e4627.

[41] Wesén E,Jeffries GDM,Matson Dzebo M,Esbjörner EK.Endocytic uptake of monomeric amyloid-β peptides is clathrin- and dynamin-independent and results in selective accumulation of Aβ(1–42) compared to Aβ(1–40).Sci Rep.2017;7:2021.

[42] LaFerla FM.Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease.Nat Rev Neurosci.2002;3:862-72.

[43] Scheff SW,Price DA,Schmitt FA,DeKosky ST,Mufson EJ.Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment.Neurology.2007;68:1501-8.

[44] Shankar GM,Li S,Mehta TH,Garcia-Munoz A,Shepardson NE,Smith I,et al.Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory.Nat Med.2008;14:837-42.

[45] Berridge MJ.Neuronal calcium signaling.Neuron.1998;21:13-26.

[46] Gutierrez-Merino C,Marques-Da-Silva D,Fortalezas S,Samhan-Arias AK.Cytosolic calcium homeostasis in neurons: Control systems, modulation by reactive oxygen and nitrogen species, and space and time fluctuations. In: Heinbockel T. editors.Neurochemistry.Rijeka:InTech2014.pp. 59-110.

[47] Magi S,Castaldo P,Macrì ML,Maiolino M,Matteucci A,Bastioli G,et al.Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease.Biomed Res Int.2016;2016:6701324.

[48] Toglia P,Cheung KH,Mak DO,Ullah G.Impaired mitochondrial function due to familial Alzheimer’s disease-causing presenilins mutants via Ca²⁺ disruptions.Cell Calcium.2016;59:240-50.

[49] Area-Gomez E,Del Carmen Lara Castillo M,Tambini MD,Guardia-Laguarta C,de Groof AJ,Madra M,et al.Upregulated function of mitochondria-associated ER membranes in Alzheimer disease.EMBO J.2012;31:4106-23.

[50] Schon EA,Area-Gomez E.Mitochondria-associated ER membranes in Alzheimer disease.Mol Cell Neurosci.2013;55:26-36.

[51] Ryan KC,Ashkavand Z,Norman KR.The Role of Mitochondrial Calcium Homeostasis in Alzheimer’s and Related Diseases.Int J Mol Sci.2020;21:9153.

[52] Poejo J,Salazar J,Mata AM,Gutierrez-Merino C.The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer’s Disease.Int J Mol Sci.2021;22:4976.

[53] O’Day DH,Eshak K,Myre MA.Calmodulin Binding Proteins and Alzheimer’s Disease.J Alzheimers Dis.2015;46:553-69.

[54] Chavez SE,O’Day DH.Calmodulin binds to and regulates the activity of beta-secretase (BACE1).Curr Res Alzheimers Dis.2007;1:37-47.

[55] Giliberto L,Borghi R,Piccini A,Mangerini R,Sorbi S,Cirmena G,et al.Mutant presenilin 1 increases the expression and activity of BACE1.J Biol Chem.2009;284:9027-38.

[56] Buggia-Prevot V,Sevalle J,Rossner S,Checler F.NFκB-dependent Control of BACE1 Promoter Transactivation by Aβ42.J Biol Chem.2008;283:10037-47.

[57] Laurén J,Gimbel DA,Nygaard HB,Gilbert JW,Strittmatter SM.Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers.Nature.2009;457:1128-32.

[58] Dunning CJ,McGauran G,Willén K,Gouras GK,O’Connell DJ,Linse S.Direct High Affinity Interaction between Aβ42 and GSK3α Stimulates Hyperphosphorylation of Tau. A New Molecular Link in Alzheimer’s Disease?ACS Chem Neurosci.2016;7:161-70.

[59] Corbacho I,Berrocal M,Török K,Mata AM,Gutierrez-Merino C.High affinity binding of amyloid β-peptide to calmodulin: Structural and functional implications.Biochem Biophys Res Commun.2017;486:992-7.

[60] Salazar J,Poejo J,Mata AM,Samhan-Arias AK,Gutierrez-Merino C.Design and Experimental Evaluation of a Peptide Antagonist against Amyloid β(1–42) Interactions with Calmodulin and Calbindin-D28k.Int J Mol Sci.2022;23:2289.

[61] Kim C,Kim Y,Lee SJ,Yun SR,Choi J,Kim SO,et al.Visualizing Heterogeneous Protein Conformations with Multi-Tilt Nanoparticle-Aided Cryo-Electron Microscopy Sampling.Nano Lett.2023;23:3334-43.

[62] Bigelow DJ,Squier TC.Redox modulation of cellular signaling and metabolism through reversible oxidation of methionine sensors in calcium regulatory proteins.Biochim Biophys Acta.2005;1703:121-34.

[63] Fradinger EA,Monien BH,Urbanc B,Lomakin A,Tan M,Li H,et al.C-terminal peptides coassemble into Aβ42 oligomers and protect neurons against Aβ42-induced neurotoxicity.Proc Natl Acad Sci U S A.2008;105:14175-80.

[64] Gessel MM,Wu C,Li H,Bitan G,Shea JE,Bowers MT.Aβ(39–42) modulates Aβ oligomerization but not fibril formation.Biochemistry.2012;51:108-17.

[65] Yankner BA,Duffy LK,Kirschner DA.Neurotrophic and Neurotoxic Effects of Amyloid β Protein: Reversal by Tachykinin Neuropeptides.Science.1990;250:279-82.

[66] Andreetto E,Yan LM,Tatarek-Nossol M,Velkova A,Frank R,Kapurniotu A.Identification of Hot Regions of the Aβ–IAPP Interaction Interface as High-Affinity Binding Sites in both Cross- and Self-Association.Angew Chem Int Ed Engl.2010;49:3081-5.

[67] Gutierrez-Merino C.Brain Hydrophobic Peptides Antagonists of Neurotoxic Amyloid β Peptide Monomers/Oligomers–Protein Interactions.Int J Mol Sci.2023;24:13846.

[68] Rammensee HG,Friede T,Stevanoviíc S.MHC ligands and peptide motifs: first listing.Immunogenetics.1995;41:178-228.

[69] Rock KL,Goldberg AL.Degradation of cell proteins and the generation of MHC class I-presented peptides.Annu Rev Immunol.1999;17:739-79.

[70] Sadowski M,Pankiewicz J,Scholtzova H,Ripellino JA,Li Y,Schmidt SD,et al.A Synthetic Peptide Blocking the Apolipoprotein E/β-Amyloid Binding Mitigates β-Amyloid Toxicity and Fibril Formation in Vitro and Reduces β-Amyloid Plaques in Transgenic Mice.Am J Pathol.2004;165:937-48.

[71] Liu S,Park S,Allington G,Prelli F,Sun Y,Martá-Ariza M,et al.Targeting Apolipoprotein E/Amyloid β Binding by Peptoid CPO_Aβ17-21 P Ameliorates Alzheimer’s Disease Related Pathology and Cognitive Decline.Sci Rep.2017;7:8009.

[72] Cai C,Dai X,Zhu Y,Lian M,Xiao F,Dong F,et al.A specific RAGE-binding peptide biopanning from phage display random peptide library that ameliorates symptoms in amyloid β peptide-mediated neuronal disorder.Appl Microbiol Biotechnol.2016;100:825-35.

[73] Tolstova AP,Adzhubei AA,Mitkevich VA,Petrushanko IY,Makarov AA.Docking and Molecular Dynamics-Based Identification of Interaction between Various Beta-Amyloid Isoforms and RAGE Receptor.Int J Mol Sci.2022;23:11816.

[74] Keck S,Nitsch R,Grune T,Ullrich O.Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer’s disease.J Neurochem.2003;85:115-22.

[75] Chondrogianni N,Petropoulos I,Franceschi C,Friguet B,Gonos ES.Fibroblast cultures from healthy centenarians have an active proteasome.Exp Gerontol.2000;35:721-8.

[76] Rock KL,York IA,Goldberg AL.Post-proteasomal antigen processing for major histocompatibility complex class I presentation.Nat Immunol.2004;5:670-7.

[77] Armstrong DM,Benzing WC,Evans J,Terry RD,Shields D,Hansen LA.Substance P and somatostatin coexist within neuritic plaques: implications for the pathogenesis of Alzheimer’s disease.Neuroscience.1989;31:663-71.

[78] Willis M,Hutter-Paier B,Wietzorrek G,Windisch M,Humpel C,Knaus HG,et al.Localization and expression of substance P in transgenic mice overexpressing human APP751 with the London (V717I) and Swedish (K670M/N671L) mutations.Brain Res.2007;1143:199-207.

[79] Oskarsson ME,Paulsson JF,Schultz SW,Ingelsson M,Westermark P,Westermark GT.In vivo seeding and cross-seeding of localized amyloidosis: a molecular link between type 2 diabetes and Alzheimer disease.Am J Pathol.2015;185:834-46.

[80] Lutz TA,Meyer U.Amylin at the interface between metabolic and neurodegenerative disorders.Front Neurosci.2015;9:216.

[81] Wang H,Muiznieks LD,Ghosh P,Williams D,Solarski M,Fang A,et al.Somatostatin binds to the human amyloid β peptide and favors the formation of distinct oligomers.Elife.2017;6:e28401.

[82] Solarski M,Wang H,Wille H,Schmitt-Ulms G.Somatostatin in Alzheimer’s disease: A new Role for an Old Player.Prion.2018;12:1-8.

[83] Lechner T,Adlassnig C,Humpel C,Kaufmann WA,Maier H,Reinstadler-Kramer K,et al.Chromogranin peptides in Alzheimer’s disease.Exp Gerontol.2004;39:101-13.

[84] Willis M,Leitner I,Jellinger KA,Marksteiner J.Chromogranin peptides in brain diseases.J Neural Transm (Vienna).2011;118:727-35.

[85] Jin JL,Liou AK,Shi Y,Yin KL,Chen L,Li LL,et al.CART treatment improves memory and synaptic structure in APP/PS1 mice.Sci Rep.2015;5:10224.

[86] Bouras C,Vallet PG,Hof PR,Charnay Y,Golaz J,Constantinidis J.Substance P immunoreactivity in Alzheimer disease: a study in cases presenting symmetric or asymmetric cortical atrophy.Alzheimer Dis Assoc Disord.1990;4:24-34.

[87] Quigley BJ Jr,Kowall NW.Substance P-like immunoreactive neurons are depleted in Alzheimer’s disease cerebral cortex.Neuroscience.1991;41:41-60.

[88] Yan LM,Velkova A,Kapurniotu A.Molecular characterization of the hetero-assembly of β-amyloid peptide with islet amyloid polypeptide.Curr Pharm Des.2014;20:1182-91.

[89] Bakou M,Hille K,Kracklauer M,Spanopoulou A,Frost CV,Malideli E,et al.Key aromatic/hydrophobic amino acids controlling a cross-amyloid peptide interaction versus amyloid self-assembly.J Biol Chem.2017;292:14587-602.

[90] Davies P,Katzman R,Terry RD.Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer disease and Alzheimer senile dementa.Nature.1980;288:279-80.

[91] Hama E,Saido TC.Etiology of sporadic Alzheimer’s disease: Somatostatin, neprilysin, and amyloid β peptide.Med Hypotheses.2005;65:498-500.

[92] Jahn H,Wittke S,Zürbig P,Raedler TJ,Arlt S,Kellmann M,et al.Peptide fingerprinting of Alzheimer’s disease in cerebrospinal fluid: identification and prospective evaluation of new synaptic biomarkers.PLoS One.2011;6:e26540.

[93] Miller B,Kim SJ,Kumagai H,Yen K,Cohen P.Mitochondria-derived peptides in aging and healthspan.J Clin Invest.2022;132:e158449.

[94] Romeo M,Stravalaci M,Beeg M,Rossi A,Fiordaliso F,Corbelli A,et al.Humanin Specifically Interacts with Amyloid-β Oligomers and Counteracts Their in vivo Toxicity.J Alzheimers Dis.2017;57:857-71.

[95] Strittmatter WJ,Saunders AM,Schmechel D,Pericak-Vance M,Enghild J,Salvesen GS,et al.Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.Proc Natl Acad Sci U S A.1993;90:1977-81.

[96] Strittmatter WJ,Weisgraber KH,Huang DY,Dong LM,Salvesen GS,Pericak-Vance M,et al.Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease.Proc Natl Acad Sci U S A.1993;90:8098-102.

[97] Wang HY,Lee DH,D’Andrea MR,Peterson PA,Shank RP,Reitz AB.β-Amyloid_1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity. Implications for Alzheimer’s disease pathology.J Biol Chem.2000;275:5626-32.

[98] Gospodarska E,Kupniewska-Kozak A,Goch G,Dadlez M.Binding studies of truncated variants of the Aβ peptide to the V-domain of the RAGE receptor reveal Aβ residues responsible for binding.Biochim Biophys Acta.2011;1814:592-609.

[99] Wang C,Shao S,Li N,Zhang Z,Zhang H,Liu B.Advances in Alzheimer’s Disease-Associated Aβ Therapy Based on Peptide.Int J Mol Sci.2023;24:13110.