Susan Catalano

The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimers Disease

The amyloid-beta (Abeta) cascade hypothesis of Alzheimers disease (AD) has dominated research and subsequent therapeutic drug development for over two decades. Central to this hypothesis is the observation that Abeta is elevated in AD patients and that the disease is ultimately characterized by the central deposition of insoluble senile plaques. More recent evidence, however, suggests that the presence or absence of plaque is insufficient to fully account for the deleterious role of elevated Abeta in AD. Such studies support the basis for an alternate interpretation of the Abeta cascade hypothesis. Namely, that soluble oligomers of Abeta (i.e., ADDLs) accumulate and cause functional deficits prior to overt neuronal cell death or plaque deposition. Accordingly, the following review focuses on research describing the preparation and functional activity of ADDLs in vitro and in vivo. These studies provide the basis for an alternate, ADDL-based, view of the Abeta cascade hypothesis and accounts for the disconnect between plaque burden and cognitive deficits. Possible therapeutic approaches aimed at lowering ADDLs in AD patients are also considered.

Discovery of ADDL-Targeting Small Molecule Drugs for Alzheimers Disease

Amyloid beta-derived diffusible ligands (ADDLs) comprise the neurotoxic subset of soluble Abeta(1-42) oligomers, now widely considered to be the molecular cause of memory malfunction and neurodegeneration in Alzheimers disease (AD). We have developed a screening cascade which identifies small molecule modulators of ADDL-mediated neurotoxicity. The primary screen involves a fluorescence resonance energy transfer (FRET)-based assay which selects inhibitors of Abeta1-42 oligomer assembly. The identified hits were further characterized by assessing their ability to inhibit the assembly and binding of ADDLs to cultures of primary hippocampal neurons. This approach has led to the identification of a number of small molecules which inhibit ADDL assembly and their subsequent binding to neurons. Here we describe our small molecule discovery efforts to identify ADDL assembly blocker and ADDL binding inhibitors, and to transform validated hits into pre-clinical lead compounds.

PROGRESSION OF SYNAPTOPROTECTIVE SIGMA-2 ANTAGONISTS INTO THE CLINIC

not available. S2-01-02 ORIGINS OF TAU ACCUMULATION Lea Tenenholz Grinberg, Memory and Aging Center, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. Contact e-mail: Lea.Grinberg@ ucsf.edu Abstract not available.not available. S2-01-03 LINKING POSTMORTEM MRI AND DENSE HISTOLOGY Paul A. Yushkevich, Penn Image Computing and Science Laborator, University of Pennsylvania, Philadelphia, PA, USA. Contact e-mail: pauly2@mail.med.upenn.edu Abstract not available.not available. S2-01-04 TAU DISSEMINATION PATTERNS IN THE BRAIN BEFORE AND AFTER DEMENTIA Val J. Lowe, Mayo Clinic, Rochester, MN, USA. Contact e-mail: vlowe@mayo.edu Abstract not available.not available. SYMPOSIUM S2-02 TRANSLATIONAL RESEARCH IN REALITY: WHATARE THE CRITERIA FROM CONCEPT TO CLINIC? S2-02-01 NEW IN VIVO MODELS FOR ALZHEIMER’S DISEASE: MODEL-AD Bruce T. Lamb, Indiana University, Stark Neurosciences Research Institute, Indianapolis, IN, USA. Contact e-mail: btlamb@iu.edu Abstract not available.not available. S2-02-02 TRANSLATIONAL RESEARCH: THE VIEW FROM PHARMA Samantha Budd Haeberlein, Biogen, Cambridge, MA, USA. Contact e-mail: samantha.buddhaeberlein@biogen.com Abstract not available. S2-02-03 PROGRESSION OF SYNAPTOPROTECTIVE SIGMA-2 ANTAGONISTS INTO THE CLINICnot available. S2-02-03 PROGRESSION OF SYNAPTOPROTECTIVE SIGMA-2 ANTAGONISTS INTO THE CLINIC Susan Catalano, Cognition Therapeutics Inc., Pittsburgh, PA, USA. Contact e-mail: scatalano@cogrx.com Background: CT1812 is a synaptoprotective therapeutic candidate for AD demonstrated to displace Ab oligomers from synaptic receptor sites, clear oligomers from brain into CSF, and restore synapse number and cognitive performance in aged transgenic mouse models of AD. Neurogranin and synaptotagmin are proteins that play a central role in synaptic function and their elevations in CSF are thought to be biomarkers of CNS synaptic damage. Preclinical studies indicate that CT1812 normalizes Ab oligomer-induced dysregulation of these synaptic proteins in neurons in vitro. Methods: A multicenter, doubleblind, placebo-controlled parallel group trial was performedwith three doses of CT1812 (90, 280 and 560mg) or placebo (N1⁄4 4 or 5 patients/ group) given once daily for 28 days to Alzheimer’s patients (MMSE 18-26). Neurogranin and synaptotagmin concentrations were measured in CSF samples from patients at baseline and following treatment with CT1812. Results:At 28 days, neurogranin and synaptotagmin levels in CSF from placebo-treated patients increased 11% and 24% compared to patients’ own baseline, while in CT1812-treated patients’ these twomarkers decreased by 18% and 19% respectively. The differences between the pooled CT1812 dose groups vs. placebo was significant for neurogranin (p1⁄40.050, ANCOVA) and for synaptotagmin-1 (F1,121⁄4 8.8, p1⁄4 0.011, linear mixed model). Conclusions:The reductions ofCSF neurogranin and synaptotagmin are consistentwith a positive effect on synapses in Alzheimer’s patients and with CT1812’s mechanism of action. This outcome was predicted by preclinical in vitro studies. Additional trials will examine the concentrations of these synaptic markers following longer term administration of CT1812 including a PET study to assess synaptic density after six months of daily treatment, and a Phase 2 trial. S2-02-04 TARGETING THE P75 NEUROTROPHIN RECEPTOR: A NEWAPPROACH FOR ALZHEIMER’S DISEASE Frank M. Longo, Stanford University, Palo Alto, CA, USA. Contact e-mail: longo@stanford.edu Abstract not available.not available. FEATURED RESEARCH SESSIONS F2-01 HORMONAL CONTRIBUTIONS TO ALZHEIMER’S DISEASE DEMENTIA RISK IN WOMEN F2-01-01 TRANSITIONS OF THE AGING FEMALE BRAIN: WINDOW INTO UNDERLYING MECHANISMS OF LATE ONSET ALZHEIMER’S DISEASE Roberta Diaz Brinton, Fei Yin, Lisa Mosconi, University of Arizona, Tucson, AZ, USA; Weill Cornell Medical College, New York, NY, USA. Contact e-mail: rbrinton@email.arizona.edu Background:Multiple neurological conditions associated with risk of Alzheimer’s can emerge during the perimenopause endocrine transition. Alzheimer’s disease prevalence is greatest in postmenopausal women and is preceded by a 10-20-year preclinical / prodromal period. The w20-year separation between menopause (w51y) and AD diagnosis