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1. SPG302 Reverses Synaptic and Cognitive Deficits Without Altering Amyloid or Tau Pathology in a Transgenic Model of Alzheimer's Disease

Author

Celia da Cunha, David Baglietto-Vargas, Marie Minh Thu Nguyen, Laura Trujillo-Estrada, Stella T. Sarraf, Peter W. Vanderklish, Run Rong Kuang, Alessandra C. Martini, Stefania Forner, Simmon Vincent F, Dominic I. Javonillo, Frank M. LaFerla, Caroline T. Nguyen, and Eric Huynh

Subjects
Synaptic deficits, Dendritic spine, Amyloid, Mice, Transgenic, tau Proteins, AMPA receptor, Hippocampus, Dendritic spines, Glutamatergic, Mice, Cognition, Postsynaptic potential, Alzheimer Disease, Medicine, Animals, Humans, Pharmacology (medical), Cognitive Dysfunction, 3xTg-AD mice, Synaptic markers, Cognitive decline, Pharmacology, Amyloid beta-Peptides, biology, business.industry, Disease Models, Animal, SPG302, Synapses, Synaptophysin, biology.protein, Original Article, Neurology (clinical), business, Cognition Disorders, Neuroscience, Postsynaptic density, Alzheimer’s disease
Abstract

Alzheimer’s disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efficacy of a novel synaptogenic small molecule, SPG302 — a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses — in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profiles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins — including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) — and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efficacious in this model without modifying Aβ and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density offer a viable strategy to reverse cognitive decline in AD. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01143-1.

Published
2021

2. Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology

Author

Alessandra C. Martini, Kristine Minh Tran, Kelly Do Huynh, Cristina Nuñez-Diaz, Franklin Garcia, Celia da Cunha, Kim N. Green, Andrea J. Tenner, Rahasson R. Ager, Stefania Forner, David Baglietto-Vargas, Dina P. Matheos, Marcelo A. Wood, Carlos J. Rodriguez-Ortiz, Laura Trujillo-Estrada, Frank M. LaFerla, Enikö A. Kramár, Jimmy Phan, Xinyi Ma, Claudio Soto, Ines Moreno-Gonzalez, Grant R. MacGregor, Vivek Swarup, Juan Antonio García-León, Lena Cai, Masashi Kitazawa, Dominic I. Javonillo, Mohammad Shahnawaz, Jessica E. Childs, Antonia Gutierrez, Ali Mortazavi, Shan Jiang, Marie Minh Thu Nguyen, Gabriela Balderrama-Gutierrez, Ken C. Walls, [Baglietto-Vargas,D, Forner,S, Cai,L, Martini,AC, Trujillo-Estrada,L, Swarup,V, Nguyen,MMT, Do Huynh,K, Javonillo,DI, Tran,KM, Phan,J, Kramár,EA, Garcia,F, Childs,J, Rodriguez-Ortiz,CJ, Kitazawa,M, Matheos,DP, Da Cunha,C, Walls,KC, Ager,RR, Tenner,AJ, Wood,M, Green,KM, LaFerla,FM] Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA. [Baglietto-Vargas,D, LaFerla,FM] Department of Neurobiology and Behavior, University of California, Irvine, CA, USA. [Baglietto-Vargas,D, Nuñez-Diaz,C, Garcia-Leon,JA, Gutierrez,A, Moreno-Gonzalez,I] Department of Cell Biology, Genetic and Physiology, Faculty of Sciences, Instituto de Investigacion Biomedica de Malaga-IBIMA, Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga, Malaga, Spain. [Jiang,S, Balderrama-Gutierrez,G, Ma,X, Mortazavi,A, MacGregor,GR] Department of Developmental and Cell Biology, University of California, Irvine, CA, USA. [Rodriguez-Ortiz,CJ, Kitazawa,M] Division of Occupational and Environmental Medicine, Department of Medicine. Center for Occupational and Environmental Health (COEH), University of California, Irvine, CA, USA. [Shahnawaz,M, Soto,C, Moreno-Gonzale,I] The Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA. [Tenner,AJ] Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA., and This study was initiated by the generosity of Harry Bubb through Cure Alzheimer’s Fund CAF-50997 (F.M.L.). Additional support was from Alzheimer’s Association NIRG-15-363477 (D.B.V.), AARF-16-440760 (S.F.) and NIRG-394284 (I.M.G.), The Larry Hillblom Foundation 2013-A-016-FEL (D.B.V.) and 2016-A-016-FEL (A.C.M.), the National Institute of Health (NIH) NIH/NIA/NINDS AG027544 (F.M.L.), AG00538 (F.M.L.), AG54884 (F.M.L.), OD010420 (F.M.L.), U54 AG054349 (F.M.L., A.J.T.), AG049562 (C.S.) NS083801 (K.N.G.) and AG056768 (K.N.G.), BrightFocus Foundation grant A2015535S (F.M.L.), by Minister of Science and Innovation grant PID2019-108911RA-100 (D.B.V.), Beatriz Galindo program BAGAL18/00052 (D.B.V.) and Institute of Health Carlos III (ISCiii) grant PI18/01557 (A.G.) co-financed by FEDER funds from European Union, by American federation of aging research-AFAR young investigator award and UC Irvine startup funds (V.S.) and UCI MIND pilot project (D.B.V.). The UCI-ADRC is funded by NIH/NIA Grant P50 AG16573 (F.M.L.). Genetically modified hAβ-KI mice were generated by the UCI Transgenic Mouse Facility, a shared resource funded in part by the Chao Family Comprehensive Cancer Center Support Grant (P30CA062203) from the National Cancer Institute. We thank Drs. Malcolm Leissring and Rodrigo Medeiros for critically reading the manuscript.

Subjects
0301 basic medicine, Male, Aging, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetic Research::Gene Ontology [Medical Subject Headings], Information Science::Information Science::Computing Methodologies::Software::Mobile Applications [Medical Subject Headings], General Physics and Astronomy, Neurodegenerative, medicine.disease_cause, Inbred C57BL, Alzheimer's Disease, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Gene Components::Exons [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression [Medical Subject Headings], Transgenic, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Exon, Mice, Amyloid beta-Protein Precursor, Cognition, 0302 clinical medicine, Enfermedad de Alzheimer, Gene expression, Organisms::Eukaryota::Animals [Medical Subject Headings], 2.1 Biological and endogenous factors, Gene Regulatory Networks, Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic [Medical Subject Headings], Aetiology, Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Nervous System Physiological Phenomena::Nervous System Physiological Processes::Neuronal Plasticity [Medical Subject Headings], Mutation, Multidisciplinary, Neuronal Plasticity, Reacción del ácido peryódico de Schiff, Brain, Alzheimer's disease, Cell biology, Chemicals and Drugs::Inorganic Chemicals::Acids::Acids, Noncarboxylic::Periodic Acid [Medical Subject Headings], Neurological, Female, Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer Disease [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], Periodic acid-schiff, Science, Transgene, Check Tags::Male [Medical Subject Headings], Cre recombinase, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Base Sequence::Regulatory Sequences, Nucleic Acid::Gene Regulatory Networks [Medical Subject Headings], Locus (genetics), Mice, Transgenic, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Gene Expression Profiling [Medical Subject Headings], Biology, Molecular neuroscience, Exones, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Alzheimer Disease, medicine, Acquired Cognitive Impairment, Genetics, Animals, Humans, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Cognición, Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::Cognition [Medical Subject Headings], Amyloid beta-Peptides, Mutación, Animal, Gene Expression Profiling, Wild type, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Amyloid beta-Peptides [Medical Subject Headings], Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], General Chemistry, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Amyloid::Amyloidogenic Proteins::Amyloid beta-Protein Precursor [Medical Subject Headings], Diseases::Animal Diseases::Disease Models, Animal [Medical Subject Headings], Brain Disorders, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Gene Ontology, Check Tags::Female [Medical Subject Headings], Synaptic plasticity, Disease Models, Dementia, Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred C57BL [Medical Subject Headings], 030217 neurology & neurosurgery, Expresión génica
Abstract

The majority of Alzheimer’s disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules., Most instances of Alzheimer’s disease (AD) are sporadic or not associated with a particular mutation. Here, the authors develop knock-in mice that express wildtype human Aβ under control of the mouse App locus, which may have potential for modelling some aspects of sporadic late onset AD.

Published
2018

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