Publications

• Buildup of toxins in Alzheimer’s disease and amytrophic lateral sclerosis have a common mechanism blocked by an investigational new drug.
  Johnson EA, Nowar R, Viola KL, Huang W, Zhou S , Bicca MA, Zhu W, Kranz DL, Klein WL, and Silverman RB. (2025). Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases. Proc Natl Acad Sci, USA. In press.
• Toxins that cause synapse loss and neuron death in AD (AβOs, pTau) have functional roles in the developing CNS.
  Bartley SC, Proctor MT, Xia H, Ho E, Kang DS, Schuster K, Bicca MA, Seckler HS, Viola KL, Patrie SM, Kelleher NL, De Mello FG, Klein WL. (2022). An Essential Role for Alzheimer’s-Linked Amyloid Beta Oligomers in Neurodevelopment: Transient Expression of Multiple Proteoforms during Retina Histogenesis. Int J Mol Sci. 23(4):2208.
• MRI and PET probes based on therapeutic antibodies can image brain AβOs.
  Viola KL, Bicca MA, Bebenek AM, Kranz DL, Nandwana V, Waters EA, Haney CR, Lee M, Gupta A, Brahmbhatt Z, Huang W, Chang TT, Peck A, Valdez C, Dravid VP, Klein WL. (2022). The Therapeutic and Diagnostic Potential of Amyloid β Oligomers Selective Antibodies to Treat Alzheimer’s Disease. Front Neurosci. 15:768646.
• Rabbit provides a non-transgenic model for risk factor-induced AD.
  Weiss C, Bertolino N, Procissi D, Aleppo G, Smith QC, Viola KL, Bartley SC, Klein WL, Disterhoft JF. (2022). Diet-induced Alzheimer’s-like syndrome in the rabbit. Alzheimers Dement (N Y). 8(1):e12241.
• Gene therapy can be used to target AβOs by expressing a selective scFv antibody in brain.
  Selles MC, Fortuna JTS, Cercato MC, Santos LE, Domett L, Bitencourt ALB, Carraro MF, Souza AS, Janickova H, Azevedo CV, Campos HC, de Souza JM, Alves- Leon S, Prado VF, Prado MAM, Epstein AL, Salvetti A, Longo BM, Arancio O, Klein WL, Sebollela A, De Felice FG, Jerusalinsky DA, Ferreira ST. (2023). AAV-mediated neuronal expression of an scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models. Mol Ther. 31(2):409-419.

• The Amyloid Beta Oligomer Hypothesis: Alzheimer’s disease is caused by neurotoxic AβOs
  Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL. (1998). Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 95(11):6448-53.

Klein WL, Krafft GA, Finch CE. (2001). Targeting small Abeta oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci. 24:219-24

• AβOs are prominent in human AD brain
  Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL. (2003). Alzheimer’s disease-affected brain: presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A. (18):10417-22.

Kelly L, Seifi M, Ma R, Mitchell SJ, Rudolph U, Viola KL, Klein WL, Lambert JJ, Swinny JD. (2021). Identification of intraneuronal amyloid beta oligomers in locus coeruleus neurons of Alzheimer’s patients and their potential impact on inhibitory neurotransmitter receptors and neuronal excitability. Neuropathol Appl Neurobiol. 47(4):488-505.

• AβOs show Alzheimer’s-dependent buildup in human CSF

Georganopoulou DG, Chang L, Nam JM, Thaxton CS, Mufson EJ, Klein WL, Mirkin CA. (2005). Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer’s disease. Proc Natl Acad Sci U S A. 102(7):2273-6.

Haes AJ, Chang L, Klein WL, Van Duyne RP. (2005). Detection of a biomarker for Alzheimer’s disease from synthetic and clinical samples using a nanoscale optical biosensor. J Am Chem Soc. 127(7):2264-71.

• AβO buildup occurs in AD models (mouse, rat, rabbit, non-human primate, C. elegans)

Chang L, Bakhos L, Wang Z, Venton DL, Klein WL. (2003). Femtomole immunodetection of synthetic and endogenous amyloid-beta oligomers and its application to Alzheimer’s disease drug candidate screening. J Mol Neurosci. 20(3):305-13.

Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, Dewilde A, Vercauteren F, Atifeh R, Ducatenzeiler A, Klein W, Szyf M, Alhonen L, and Cuello AC. (2010). A Novel Transgenic Rat Model with a Full Alzheimer’s-Like Amyloid Pathology Displays Pre-Plaque Intracellular Amyloid-beta-Associated Cognitive Impairment. J Alzheimers Dis. 20(1):113-26.

Forny-Germano L, Lyra e Silva NM, Batista AF, Brito-Moreira J, Gralle M, Boehnke SE, Coe BC, Lablans A, Marques SA, Martinez AM, Klein WL, Houzel JC, Ferreira ST, Munoz DP, De Felice FG. (2014). Alzheimer’s disease-like pathology induced by amyloid-β oligomers in nonhuman primates. J Neurosci. 34(41):13629-43.

Bitel CL, Kasinathan C, Kaswala RH, Klein WL, and Frederikse PH. (2012) Amyloid-β and tau pathology of Alzheimer’s disease induced by diabetes in a rabbit animal model. J Alzheimers Dis. 32(2):291-305.

Wu Y, Wu Z, Christen Y, Lambert MP, Klein WL, Link CD, and Luo Y. (2006) Amyloid beta-induced pathological behaviors are suppressed by Ginkgo Biloba extract EGb 761 and ginkgolide in transgenic Caenorhabditis Elegans. J. Neurosci. 26(50): 13102-13.

• AβOs impair synaptic mechanisms of memory … LTP and LTD
  Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL. (1998). Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A, 95(11):6448-53.

Wang HW, Pasternak JF, Kuo H, Ristic H, Lambert MP, Chromy B, Viola KL, Klein WL, Stine WB, Krafft GA, Trommer BL. Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain research. 2002;924(2):133-40.

• AβOs instigate AD neuropathology …  tau hyper-phosphorylation, synapse loss, receptor trafficking, selective nerve cell death, and inflammatory gliosis
  De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, Bigio EH, Jerecic J, Acton PJ, Shughrue PJ, Chen-Dodson E, Kinney GG, Klein WL. (2008). Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiology of aging. 29(9):1334-47.

Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL. (2007). Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci. 27(4):796-807.

Renner M, Lacor PN, Velasco PT, Xu J, Contractor A, Klein WL, Triller A. (2010). Deleterious effects of amyloid β oligomers acting as an extracellular scaffold for mGluR5. Neuron, 66(5):739-54.

Kim HJ, Chae SC, Lee DK, Chromy B, Lee SC, Park YC, Klein WL, Krafft GA, Hong ST. (2003). Selective neuronal degeneration induced by soluble oligomeric amyloid beta protein. FASEB J. 17(1):118-20.

Ferretti MT, Bruno MA, Ducatenzeiler A, Klein WL, and Cuello AC. (2012) Intracellular Aβ-oligomers and early inflammation in a model of Alzheimer’s disease. Neurobiol Aging. 33(7):1329-42.

• AβOs promote Type 3 Diabetes (brain insulin resistance)
  Zhao W, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon M, Krafft GA, and Klein WL. (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 22:246-60.

Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG. (2012). An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Aβ oligomers. J Clin Invest. 122(4):1339-53.

• AβO neurotoxicity blocked by insulin
  De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ, Ferreira ST, Klein WL. (2009). Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Aβ oligomers. Proc Natl Acad Sci U S A. 106(6):1971-6.

Zhao W-Q, Lacor PN, Chen H, Lambert MP, Quon MJ, Krafft GA, and Klein WL. (2009) Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric Abeta. J Biol Chem. 284(28):18742-53.

Pitt J, Wilcox KC, Tortelli V, Diniz LP, Oliveira MS, Dobbins C, Yu XW, Nandamuri S, Gomes FCA, DiNunno N, Viola KL, De Felice FG, Ferreira ST, Klein WL. (2017). Neuroprotective astrocyte-derived insulin/insulin-like growth factor 1 stimulates endocytic processing and extracellular release of neuron-bound Aβ oligomers. Mol Biol Cell. 28(20):2623-2636.

Batista AF, Forny-Germano L, Clarke JR, Lyra E Silva NM, Brito-Moreira J, Boehnke SE, Winterborn A, Coe BC, Lablans A, Vital JF, Marques SA, Martinez AM, Gralle M, Holscher C, Klein WL, Houzel JC, Ferreira ST, Munoz DP, De Felice FG. (2018). The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer’s disease. J Pathol. 245(1):85-100.

• AβOs are ligands with synaptic and molecular specificity
  Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL. (2004) Synaptic targeting by Alzheimer’s-related amyloid β oligomers. J Neurosci. 24(45):10191-200.

Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL. (2003). Alzheimer’s disease-affected brain: presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A. (18):10417-22.

Renner M, Lacor PN, Velasco PT, Xu J, Contractor A, Klein WL, and Triller A. (2010) Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron. 66(5):739-54.

Decker H, Jurgensen S, Adrover MF, Brito-Moreira J, Bomfim TR, Klein WL, Epstein AL, De Felice FG, Jerusalinsky D, Ferreira ST. N-methyl-D-aspartate receptors are required for synaptic targeting of Alzheimer’s toxic amyloid-beta peptide oligomers. J Neurochem. 2010;115(6):1520-9.

DiChiara T, DiNunno N, Clark J, Bu RL, Cline EN, Rollins MG, Gong Y, Brody DL, Sligar SG, Velasco PT, Viola KL, Klein WL. (2017). Alzheimer’s Toxic Amyloid Beta Oligomers: Unwelcome Visitors to the Na/K ATPase alpha3 Docking Station. Yale J Biol Med. 90(1):45-61.

• AβOs from AD brain: Ligands with 12mer subunits … synthetic, fibril-free analogs mimic brain-derived AβOs
  Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL. (2003). Alzheimer’s disease-affected brain: presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A, (18):10417-22.

Klein WL. (2002). Aβ toxicity in Alzheimer’s Disease: emergence of globular oligomer (ADDLs) as new vaccine and drug targets. Neurochem Intl. 41:345-352.

Chromy BA, Nowak RJ, Lambert MP, Viola KL, Chang L, Velasco PT, Jones BW, Fernandez SJ, Lacor PN, Horowitz P, Finch CE, Krafft GA, Klein WL. (2003). Self-assembly of Abeta(1-42) into globular neurotoxins. Biochemistry. 42(44):12749-60.

• AβO binding impacts Fyn, Arc, Ca++, ROS and ER stress
  Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL. (1998). Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 95(11):6448-53.

Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL. (2004) Synaptic targeting by Alzheimer’s-related amyloid β oligomers. J Neurosci. 24(45):10191-200.

De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL. (2007). Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem. 282(15):11590-601.

Costa RO, Lacor PN, Ferreira IL, Resende R, Auberson YP, Klein WL, Oliveira CR, Rego AC, Pereira CM. (2012). Endoplasmic reticulum stress occurs downstream of GluN2B subunit of N-methyl-d-aspartate receptor in mature hippocampal cultures treated with amyloid-beta oligomers. Aging cell. 11(5):823-33.

• AβO vaccination generates highly selective AβO antibodies
  Lambert MP, Viola KL, Chromy BA, Chang L, Morgan TE, Yu J, Venton DL, Krafft GA, Finch CE, Klein WL. (2001). Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies. J Neurochem. 79(3):595-605.

Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, Khuon D, Gong Y, Bigio EH, Shaw P, De Felice FG, Krafft GA, Klein WL. (2007). Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem. 100(1):23-35.

Wang X.P., Zhang J.H., Wang Y.J., Feng Y., Zhang X., Sun X.X., Li J.L., Du X.T., Lambert M.P., Yang S.G., Zhao M., Klein W.L., and Liu R.T. (2009). Conformation-dependent single-chain variable fragment antibodies specifically recognize beta-amyloid oligomers. FEBS Lett. 583(3):579-84.

Sebollela A, Cline EN, Popova I,  Luo K,  Sun X,  Ahn J, Barcelos MA, Bezerra VN, Lyra e Silva NM, Patel J, Pinheiro NR, Qin AL, Kamel JM, Weng A,  Bebenek AM, Velasco PT, Viola KL, Lacor PN, Ferreira ST, Klein WL. (2017). A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-β oligomers. J Neurochem. 142(6):934-947.

• AβOs in brain can be imaged using antibody-based probes for MRI and PET
  Viola KL, Sbarboro J, Sureka R, De M, Bicca MA, Wang J, Vasavada S, Satpathy S, Wu S, Joshi H, Velasco PT, MacRenaris K, Waters EA, Lu C, Phan J, Lacor P, Prasad P, Dravid VP, Klein WL. (2015). Towards non-invasive diagnostic imaging of early-stage Alzheimer’s disease. Nat Nanotechnol. 10(1):91-8.

Viola KL, Bicca MA, Bebenek AM, Kranz DL, Nandwana V, Waters EA, Haney CR, Lee M, Gupta A, Brahmbhatt Z, Huang W, Chang TT, Peck A, Valdez C, Dravid VP, Klein WL. (2022). The Therapeutic and Diagnostic Potential of Amyloid β Oligomers Selective Antibodies to Treat Alzheimer’s Disease. Front Neurosci. 15:768646.

• AβO antibodies rescue memory in AD models.
  Xiao C, Davis FJ, Chauhan BC, Viola KL, Lacor PN, Velasco PT, Klein WL, and Chauhan NB. (2013). Brain transit and ameliorative effects of intranasally delivered anti-amyloid-β oligomer antibody in 5XFAD mice. J Alzheimers Dis. 35(4):777-88.

Viola KL, Bicca MA, Bebenek AM, Kranz DL, Nandwana V, Waters EA, Haney CR, Lee M, Gupta A, Brahmbhatt Z, Huang W, Chang TT, Peck A, Valdez C, Dravid VP, Klein WL. (2022). The Therapeutic and Diagnostic Potential of Amyloid β Oligomers Selective Antibodies to Treat Alzheimer’s Disease. Front Neurosci. 15:768646.

Selles MC, Fortuna JTS, Cercato MC, Santos LE, Domett L, Bitencourt ALB, Carraro MF, Souza AS, Janickova H, Azevedo CV, Campos HC, de Souza JM, Alves- Leon S, Prado VF, Prado MAM, Epstein AL, Salvetti A, Longo BM, Arancio O, Klein WL, Sebollela A, De Felice FG, Jerusalinsky DA, Ferreira ST. (2023). AAV-mediated neuronal expression of an scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models. Mol Ther. 31(2):409-419.

• Successful completion of Phase 1 of the “Intercept-AD” clinical trial by Acumen (an Alzheimer’s biotech I co-founded), which tests an AβO monoclonal antibody, sabirnetug (ACU193), that was developed based on original research from my team at Northwestern.
  Sabirnetug. (2024). Alzforum. (n.d.). Nov 14, 2024. from https://www.alzforum.org/therapeutics/sabirnetug

Westwicke I. Acumen Pharmaceuticals to Present Sabirnetug (ACU193) Fluid Biomarker and Target Engagement Analyses from Phase 1 INTERCEPT-AD Study in Early Alzheimer’s at the AD/PD™ 2024 Annual Meeting. In: Acumen Pharmaceuticals I, editor. https://investors.acumenpharm.com/news-releases/news-release-details/acumen-pharmaceuticals-present-sabirnetug-acu193-fluid-biomarker: Globe Newswire; 2024.

• Discovery that transiently expressed AβOs play a role in CNS development.
  Pope WP, Enam SA, Bawa N, Miller BE, Ghanbari HA, and Klein WL. (1993). Phosphorylated  tau epitope  of Alzheimer’s disease is couple to axon development in the avian central nervous system. Expt. Neurol.  120:106-113.

Bartley SC, Proctor MT, Xia H, Ho E, Kang DS, Schuster K, Bicca MA, Seckler HS, Viola KL, Patrie SM, Kelleher NL, De Mello FG, Klein WL. An Essential Role for Alzheimer’s-Linked Amyloid Beta Oligomers in Neurodevelopment: Transient Expression of Multiple Proteoforms during Retina Histogenesis. International journal of molecular sciences. 2022;23(4). Epub 2022/02/27. doi: 10.3390/ijms23042208

Klein WL. A time for optimism in the dementia field. Front Dement. 2022 Oct 18;1:1038003. doi: 10.3389/frdem.2022.1038003.

Cline EN, Bicca MA, Viola KL, Klein WL. (2018). The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade.  J Alzheimers Dis. 64(s1):S567-S610. doi: 10.3233/JAD-179941.

Viola KL, Klein WL. (2015) Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol. 129(2):183-206. doi: 10.1007/s00401-015-1386-3.

WL Klein. (2014).  Targeting Aß oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease. Henry Stewart Talks – The Biomedical & Life Sciences Collection. hstalks.com

Ferreira ST, Klein WL. (2011). The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem, 96(4):529-43.

Klein WL, Krafft GA, Finch CE. (2001). Targeting small Abeta oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci. 24(4):219-24.