Cognition Therapeutics Publications
Limegrover, CS, LeVine, H, III, Izzo, NJ, Yurko, R, Mozzoni, K, Rehak, C, Sadlek, K, Safferstein, H and Catalano, SM (2020), Alzheimer’s Protection Effect of A673T Mutation May Be Driven by Lower Aβ Oligomer Binding Affinity. Journal of Neurochemistry. Accepted Author Manuscript. doi:10.1111/jnc.15212
Colom-Cadena M, Spires-Jones T, Zetterberg H, Blennow K, Caggiano A, DeKosky ST, Fillit H, Harrison JE, Schneider LS, Scheltens P,
de Haan W, Grundman M, van Dyck CH, Izzo NJ, Catalano SM and the Synaptic Health Endpoints Working Group. The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease. Alz Res Therapy 12, 21 (2020)
Grundman M, Morgan R, Lickliterd JD, Schneider LS, DeKosky S, Izzo NJ, Guttendorf R, Higgin M, Pribyli J, Mozzoni J, Safferstein H, Catalano SM. A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer’s disease. Alzheimers Dement (N Y). 2019 Jan 23; 5:20-26
Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, Rehak C, Yurko R, Look G, Rishton G, Safferstein H, Cruchaga C, Goate A, Cahill MA, Arancio O, Mach RH, Craven R, Head E, LeVine H 3rd, Spires-Jones TL, Catalano SM. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity PLoS One. 2014 Nov 12; 9(11):e111899
Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd, Vaswani A, Wardius M, Syed Z, Ravenscroft J, Mozzoni K, Silky C, Rehak C, Yurko R, Finn P, Look G, Rishton G, Safferstein H, Miller M, Johanson C, Stopa E, Windisch M, Hutter-Paier B, Shamloo M, Arancio O, LeVine H 3rd, Catalano SM. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits PLoS One. 2014 Nov 12; 9(11):e111898
Relevant Industry Publications
Foundational Principles of Neuroscience:
Takeuchi T, Duszkiewicz AJ, et al. The synaptic plasticity and memory hypothesis: encoding, storage and persistence. Philos Trans R Soc Lond B Biol Sci. 2013 Dec 2; 369(1633)
Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science. 2001 Nov 2;294(5544):1030-8
Bliss TV, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforantpath. J Physiol. 1973 Jul; 232(2):331-56.
Ramón y Cajal S The structure and connexions of neurons (Lecture delivered December 12, 1906). In: (eds) Nobel Lectures, Physiology or Medicine 1901–1921. Elsevier Publishing Company, Amsterdam-London-New York
Genetic Basis of Alzheimer's Disease:
Karch CM, Cruchaga C, et al. Alzheimer’s Disease Genetics: From the bench to the clinic. Neuron. 2014 Jul 2; 83(1): 11–26
Tanzi, RE. The Genetics of Alzheimer Disease. Cold Spring Harb Perspect Med. 2012 Oct 1; 2(10)
Synapse Loss Correlates to Cognitive Deficit:
de Wilde MC, et al. Meta-analysis of synaptic pathology in Alzheimer’s disease reveals selective molecular vesicular machinery vulnerability. Alzheimers Dement. 2016 Jun;12(6):633-44
Scheff SW, et al. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology. 2007 May 1; 68(18):1501-8
Scheff SW, et al. Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging. 2006 Oct; 27(10):1372-84
DeKosky ST and Price DA. Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging. 2003 Dec; 24(8):1029-46
Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002; 298:789–791
Rössler M, et al. Stage-dependent and sector-specific neuronal loss in hippocampus during Alzheimer’s disease. Acta Neuropathol. 2002 Apr; 103(4):363-9
DeKosky ST, Scheff SW, Styren SD. Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration. 1996 Dec; 5(4):417-21
Lassmann H, Fischer P, Jellinger K. Synaptic pathology of Alzheimer’s disease. Ann N Y Acad Sci. 1993 Sep 24;695:59-64
Terry RD, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–580
DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Annals of Neurology. 1990 May; 27(5):457-64
Monomers, Oligomers, Fibrils and Plaques - the Aβ Equilibrium:
Esparza TJ, Gangolli M, et al. Soluble amyloid-beta buffering by plaques in Alzheimer disease dementia versus high-pathology controls. PLoSOne. 2018 Jul 6; 13(7)
Brody DL, Jiang H, et al. Non-canonical soluble amyloid-beta aggregates and plaque buffering: controversies and future directions for target discovery in Alzheimer’s disease. Alzheimers Res Ther. 2017 Aug 17; 9(1):62
van Maanen EM, van Steeg TJ, et al. Systems Pharmacology Analysis of the Amyloid Cascade after β-Secretase Inhibition Enables the Identification of an Aβ42 Oligomer Pool. J Pharmacol Exp Ther. 2016 Apr; 357(1):205-16
Aβ Accumulates and Self-Associates into Oligomers
Brinkmalm G, Hong W, et al. Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer’s brain. Brain. 2019 May 1;142(5):1441-1457
Savioz A, Giannakopoulos P, et al. A Study of Aβ Oligomers in the Temporal Cortex and Cerebellum of Patients with Neuropathologically Confirmed Alzheimer’s Disease Compared to Aged Controls. Neurodegener Dis. 2016; 16(5-6):398-406
Esparza TJ, Zhao H, et al. Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol. 2013 Jan; 73(1):104-19
Tomic JL, Pensalfini A, et al. Soluble fibrillar oligomer levels are elevated in Alzheimer’s disease brain and correlate with cognitive dysfunction. Neurobiol Dis. 2009 Sep; 35(3):352-8
Aβ Oligomers Bind to a Receptor Complex on Synapses:
Smith LM, Kostylev MA, et al. Systematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer’s disease relevance. J Biol Chem. 2019 Apr 12; 294(15):6042-6053
Zhao J, Li A, et al. Soluble Aβ Oligomers Impair Dipolar HeterodendriticPlasticity by Activation of mGluRin the Hippocampal CA1 Region. iScience. 2018 Aug 31; 6:138-150
Smith LM, Strittmatter SM. Binding Sites for Amyloid-β Oligomers and Synaptic Toxicity. Cold Spring Harb Perspect Med. 2017 May 1; 7(5)
Bound Aβ Oligomers are Toxic to Synapses:
Cline EN, Bicca MA, et al. The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade. J Alzheimers Dis. 2018; 64(s1):S567-S610
Selkoe DJ, Hardy J. The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years. EMBO Molecular Medicine. 2016 Jun; 8(6):595-608
Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron. 2014 May 21; 82(4):756-71
Mucke L, Selkoe DJ. Neurotoxicity of Amyloid β-Protein: Synaptic and Network Dysfunction. Cold Spring Harb Perspect Med. 2012 Jul; 2(7):a006338
Walsh DM, Klyubin I, et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002 Apr 4; 416(6880):535-9
Lambert MP, Barlow AK, et al. Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA. 1998 May 26; 95(11):6448-53
Sigma-2 Receptor Complex Biology and Role in Disease:
Alon A, Schmidt HR, et al. Identification of the gene that codes for the σ2 receptor. Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7160-7165
Riad A, Zeng C, et al. Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex. Sci Rep. 2018 Nov 15;8(1):16845
Role of Tau in Alzheimer's Cascade:
Ittner A, Ittner LM. Dendritic Tau in Alzheimer’s Disease. Neuron. 2018 Jul 11; 99(1):13-27
McInnes J, Wierda K, et al. Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau. Neuron. 2018 Feb 21; 97(4):823-835
Zhou L, McInnes J, et al. Tau association with synaptic vesicles causes presynaptic dysfunction. Nat Commun. 2017 May 11; 8:15295
Tai HC, Serrano-Pozo A, et al. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am J Pathol. 2012 Oct; 181(4):1426-35
Kopeikina KJ, Hyman BT, et al. Soluble forms of tau are toxic in Alzheimer’s disease. Transl Neurosci. 2012 Sep; 3(3):223-233
Biomarkers of Disease and Target Engagement:
Schindler SE, Li Y, et al; Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer’s disease. Alzheimers Dement. 2019 May;15(5):655-665
Dhiman K, Blennow K, et al. Cerebrospinal fluid biomarkers for understanding multiple aspects of Alzheimer’s disease pathogenesis. Cell Mol Life Sci. 2019 May;76(10):1833-1863
Chen MK, Mecca AP, et al. Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging. JAMA Neurol. 2018 Oct 1; 75(10):1215-1224
Mormino EC, Jagust WJ. A New Tool for Clinical Neuroscience-Synaptic Imaging. JAMA Neurol. 2018 Oct 1; 75(10):1181-1183
Toledo JB, Arnold M, et al. Metabolic network failures in Alzheimer’s disease: A biochemical road map. Alzheimers Dement. 2017 Sep; 13(9):965-984
Russell CL, Mitra V, et al. Comprehensive Quantitative Profiling of Tau and Phosphorylated Tau Peptides in Cerebrospinal Fluid by MassSpectrometry Provides New Biomarker Candidates. J Alzheimers Dis. 2017; 55(1):303-313
Öhrfelt A, Brinkmalm A, et al. The Pre-Synaptic Vesicle Protein Synaptotagmin is a Novel Biomarker for Alzheimer’s Disease. Alzheimer’s Research & Therapy. 2016; Oct 3; 8(1):41
Janelidze S, Hertze J, et al Cerebrospinal Fluid Neurogranin and YKL-40 as Biomarkers of Alzheimer’s Disease. Annals of Clinical and Translational Neurology. 2015 Nov 20; 3(1):12-20