APP mouse models for Alzheimer's disease preclinical studies

The EMBO Journal, Journal Year: 2017, Volume and Issue: 36(17), P. 2473 - 2487

Published: Aug. 2, 2017

Review2 August 2017Open Access APP mouse models for Alzheimer's disease preclinical studies Hiroki Sasaguri Corresponding Author [email protected] orcid.org/0000-0003-2550-9156 Laboratory Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Japan Department of Neurology and Neurological Science, Graduate School Medicine, Tokyo Medical Dental University, Tokyo, Search more papers by this author Per Nilsson orcid.org/0000-0001-6450-0870 Division Neurogeriatrics, Neurobiology, Care Sciences Society, Center Alzheimer Research, Karolinska Institutet, Huddinge, Sweden Shoko Hashimoto orcid.org/0000-0002-5778-4884 Kenichi Nagata orcid.org/0000-0001-8377-7197 Takashi Saito orcid.org/0000-0002-9659-9251 Neuroscience Pathobiology, Research Institute Environmental Nagoya Nagoya, Bart De Strooper orcid.org/0000-0001-5455-5819 Dementia University College London, UK Neurosciences, KU Leuven, Belgium VIB Disease John Hardy orcid.org/0000-0002-3122-0423 Reta Lila Laboratories the Molecular London Neurology, Robert Vassar Cell Biology, Feinberg Northwestern Chicago, IL, USA Bengt Winblad orcid.org/0000-0002-0011-1179 Takaomi C Saido orcid.org/0000-0003-1970-6903 Information *,1,2, Nilsson1,3, Hashimoto1, Nagata1, Saito1,4, Strooper5,6,7, Hardy8, Vassar9, Winblad3 *,1 1Laboratory 2Department 3Division 4Department 5Dementia 6Department 7VIB 8Reta 9Department *Corresponding author. Tel: +81 48 4621111 (ext 7613); E-mail: 4679715; The EMBO Journal (2017)36:2473-2487https://doi.org/10.15252/embj.201797397 PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Animal human diseases that accurately recapitulate clinical pathology are indispensable understanding molecular mechanisms advancing studies. (AD) research community has historically used first-generation transgenic (Tg) overexpress proteins linked familial AD (FAD), mutant amyloid precursor protein (APP), or presenilin (PS). These mice exhibit pathology, but overexpression paradigm may cause additional phenotypes unrelated AD. Second-generation contain humanized sequences mutations in endogenous App gene. show Aβ accumulation without related not yet a recapitulation In review, we evaluate different AD, review recent using second-generation mice. We advise researchers consider comparative strengths limitations each model against scientific therapeutic goal prospective study. Modeling with is most common neurodegenerative disease. 2015, ~47 million individuals dementia worldwide (Prince et al, 2016), accounted 50–70% these cases (Winblad 2016). coming decades, global prevalence projected reach higher epidemic levels will place massive economic burden on society. Given grim epidemiological forecast, scientifically based strategies prevent urgently needed, as evidenced fact previous two decades than 400 medication candidates failed clinic (Mangialasche 2010). This large-scale failure pharmaceutical industry biomedical can be attributed many factors, including inappropriate choice models, wrong timing interventions, over-reliance assays translational studies, lack precise biomarkers, which center efficacy reproducibility animal were critical component. focus important roles genetically engineered have contributed mechanistic drug development. Recently, new been introduced community, summarize construction, characteristics, merits demerits current facilitate tools design future aim, guided principle should ideally prevented stages where potential interventional window at least 20 years exists before clinically manifests (Funato 1998; Bateman 2012). Clinically, characterized early memory deficits followed decline other cognitive functions (Scheltens 2016; begins overt symptoms includes β peptide (Aβ) extracellular plaques, hyper-phosphorylated tau intracellular neurofibrillary tangles (NFTs), chronic neuroinflammation, loss neuronal cells mainly cerebral cortex hippocampus (Braak Braak, 1991; Hyman parallel, coordinated breakdown vascular, astroglial, oligodendrocytic responses demonstrates systems disorder interactions cell types brain homeostasis resultant major topic (De Karran, initiated cortical onset (Bateman 2012; Maruyama 2013). After onset, it increasingly difficult treat after postmitotic neurons start degenerate (Fig 1) finely tuned circuits skills easily recovered later stages. Thus, development accurate medications prevention treatment considered vital goals accord status. Figure 1. Cortical neurological symptoms, ADThere three phases leading associated pathology. first phase accumulates symptoms. second mild impairment (MCI), tauopathy neurodegeneration proceed predementia third eliminates an irreversible manner progressively serious dementia. As APP-overexpressing knock-in extensive neurodegeneration, there preventive approximately decades. Modified from Ihara Arai (2007). shown 9-month-old AppNL-G-F/NL-G-F mouse. Blue: Aβ; red: microglia (Iba-1); green: astrocyte (GFAP) (Saito 2014). Download figure PowerPoint Sporadic late-onset (LOAD) accounts 99% all (Campion 1999), ratio LOAD patients continues increase because aging primary risk factor aligned world population. Early-onset (EOAD), contrast, predominately caused genes encode (App), presenilin-1 (PSEN1 PS1) presenilin-2 (PS2). processing β-secretase (β-site cleaving enzyme 1 BACE1) γ-secretase generates soluble fragments. γ-Secretase complex composed PS1 PS2, nicastrin, Aph1 enhancer 2 (PEN2). Most (FAD) affect processivity resulting release longer peptides shift relative ratios peptides, Aβ42/Aβ40 (Welander 2009; Chávez-Gutiérrez Similarly, gene result production aggregate (Rosenberg Interestingly, AppA673T mutation was claimed reduce sporadic (SAD) age-related decreasing (Jonsson 2012), although findings require confirmation (Wang 2015) appears biophysical properties (Benilova 2014; Maloney existence directly influence often cited evidence central pathogenesis (amyloid cascade hypothesis: Selkoe Hardy, general, morphologically similar, rationalizing use FAD SAD. However, extent actually reproduce SAD remains unknown. A developing mechanism accumulation. FAD, deposition primarily increased Aβ>40 except intra-Aβ sequence alter its structural (Selkoe 2016) Swedish increases species increasing cleavage β-site. Whether Iceland protective 2012) controversial. degradation declines potentially due decrease Aβ-degrading neprilysin (Iwata 2001, 2002; Hellström-Lindahl 2008) clearance decreased (Mawuenyega 2010), likely partially aging-associated degradation/clearance 2). accord, might contribute (Saido Iwata, 2006). Recent ubiquitin-proteasome system autophagy (Nilsson 2013; Ciechanover Kwon, 2015; Khaminets point essential significance While dominant SAD, FAD-like production. selection issue. 2. proteostasis determined balance degradationThe anabolism catabolism determines steady-state quantity given biological system. pathogenic (Aβ42 Aβ43) results pathological deposition. causes fully understood, candidate 2006; 2008). Various (Onos Puzzo Drummond Wisniewski, 2017) well rats, non-human primates, Drosophila, Caenorhabditis elegans (Drummond recently reviewed. modified they practical approach vivo screening validation time (Zahs Ashe, absence manipulations, no small exist present sufficiently consistently mimic experimental Furthermore, stage when effective wider. Preclinical cognitively normal likewise, parallel having strong impairment. stage, alterations thought initiate processes synaptic dysfunction, local damage spines dendrites, vascular observed presumably presymptomatic humans (Ashe Zahs, There points such mechanism(s) amyloidosis affects TREM2 (Guerreiro Jonsson Stefansson, 2013) influences also studied First-generation First, note terminology: term "transgenic mice" could confusing wide sense means "genetically into host genome transgene inserted single multicopy number. definition Tg knockout maintain original murine genomic structure mutations. Several groups generated various promoters (Table 1), platelet-derived growth factor-β (PDGF-β), prion (PrP), Thy1. Frequently include PDAPP (Games 1995), Tg2576 (Hsiao 1996), APP23 (Sturchler-Pierrat 1997), J20 (Mucke 2000), TgCRND8 (Chishti 2001). constructs differ among lines: They APP695, APP770, minigenes. Some carry one transgene, commonly (K670N/M671L; Citron 1992), overproduction total APP. deposits brain, reminiscent plaques some differences (refer section "Limitations models"). addition, develop dysfunction appearance cases. unable tangle (NFT) formation loss. Table Comparison Strain(s) Genetic background Promoter Mutation(s) General features Potential disadvantages Suitable applications Single APP-Tg C57B6 × DBA2 PDGF-β APPV717F Moderate behavioral phenotype Neuronal Random integration Overexpression-related artifacts: multiple fragments overproduced No perfect negative control Artificial expression pattern controlled exogenous NFTs, feature Sudden death (unknown reason): Tg2576, Cognitive preceding Mixed genetic backgrounds Analysis production, deposition, Aβ-associated neuroinflammation Drug (targeting secretases) behavior if Identification CSF biomarkers B6; SJL mixed hamster (PrP) APPKM670/671NL C57BL/6 Thy1 APPKM670/671NL,V717F Hybrid C3H/He-C57BL/6 Double PSEN1-Tg KI APPPS1 C57BL/6J (APP, PS1I166P number transgenes Multiple (APP + Non-specific ER stress arise Complicated crossbreeding death, 5XFAD (C57BL/6 SJL)F1 Thy1.2 APPKM670/671NL,I716V,V717I PS1M146L,L286V Triple 3xTg-AD Tau) (PS1) APPK670N,M671L PS1M146V MAPTP301L severe NFT FTDP-17) FTDP-17 tau) Tau imaging NL-F APPKM670/671NL,I716F Minor byproducts CTFβ Endogenous promoter-driven Presence relevant (NL mice) Two lines differential purposes (wild-type Aβ) NL-G-F (Arctic : APP, interaction between identified Unknown effects Arctic phenotypes, NFTs loss, Genomic homozygosity order accelerate remove (heterozygous accumulate Aβ, take homozygous mice.) Overproduction pathways neural network Omics analysis Reverse (preventive) Additional manipulations (gene editing) transcription splicing plasma APPKM670/671NL,E693G,I716F side-by-side comparison key factors selecting Researchers decide depending specific goal. only part efforts made combine them further reconstitute remaining hallmarks. constituent cleaves terminal fragment (CTF-β) produce 1998). majority (Karch PSEN1 alone did induce absolute amount Aβ42 Aβ43 insufficient 1995). Alternately, low amyloidogenic amino acids compared (Chui 1999; Guo Schmitz 2004; Xu 2015). combination conferred amyloidogenicity, resulted accelerated deficits, combinations PS1M146L (Holcomb 1998), PSA246E (Borchelt 1996, APP751KM670/671NL-V717I PSM146L (Schmitz 2004), KM670/671NL-V717I PSEN1M233T/L235P (Casas 2004). Oakley al (2006) carrying five (APPK670N/M671L/I716V/V717I PSEN1M146L/L286V Tg) driven Thy-1 promoter. exhibited gliosis months age, degeneration developed progressive 4–5 months. despite their aggressive changes replicate Tau-Tg enhanced limbic olfactory affecting (Tg2576 JNPL3: Lewis 2001; Bolmont 2007). Oddo (2003) triple model, mice, APPswe, TauP301L background. neuropathology similar patients, together gliosis, damage, deficits. Mapt rather frontotemporal parkinsonism chromosome 17 (FTDP-17). artificial phenomena making interpret results. crossbred improvements survival suggests possibly confer toxicity (J20: Roberson 2007; APP23: Ittner combinations, BACE1 (Ohno 2004) apolipoprotein E4 (ApoE4) (Fryer 2005), useful applications. Studies APP- APP/PS-overexpressing allowed applied research. Although details plaque age size regional distribution, content vary line, aspects accumulation, (microgliosis astrogliosis). cases, downstream pathologic consequences overexpressing hyperphosphorylation, dystrophic neurites, markers, (Zhao 2007), appear those Other For example, neuron (Oakley Importantly, abolishes same prevents both responsible lines, overexpression, β-CTF cannot ruled out. validating assessing inhibition strategy abrogates tested date (Luo 2003; Ohno 2004, Laird 2005; McConlogue Rabe 2011), brain. Subsequently, screen molecule inhibitors BACE1, 90% more. advanced trials lowering (May Neumann Kennedy Cebers 2017). Another application translated successfully testing anti-Aβ antibody aducanumab. Plaque-bearing chronically treated aducanumab experienced dose-dependent reduction up ~70% vehicle (Sevigny aducanumab-mediated appeared involve binding aged brains stimulating microglial phagocytosis Aβ. Criticisms focused γ-secretase-based medications. work follow models) had predicted almost side seen trials, long III

Language: Английский

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Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade

Chemical Reviews, Journal Year: 2018, Volume and Issue: 119(2), P. 1221 - 1322

Published: Aug. 10, 2018

Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow negative outlook. Although large amount research has been dedicated to elucidating pathologies neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, neurotransmitter deficiencies are pathological features shared across multiple disorders. In addition, these factors proposed be interrelated upon disease progression. Thus, development multifunctional compounds capable simultaneously interacting with several components suggested as solution undertake complex diseases. this review, we outline discuss possible therapeutic targets in Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis molecules, previously designed or discovered potential drug candidates for disorders emphasis multifunctionality. underrepresented areas discussed indicate new directions.

Language: Английский

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ApoE4: an emerging therapeutic target for Alzheimer’s disease

BMC Medicine, Journal Year: 2019, Volume and Issue: 17(1)

Published: March 20, 2019

The growing body of evidence indicating the heterogeneity Alzheimer's disease (AD), coupled with disappointing clinical studies directed at a fit-for-all therapy, suggest that development single magic cure suitable for all cases may not be possible. This calls shift in paradigm where targeted treatment is developed specific AD subpopulations share distinct genetic or pathological properties. Apolipoprotein E4 (apoE4), most prevalent risk factor AD, expressed more than half patients and thus an important possible therapeutic target. review focuses initially on effects apoE4 as well corresponding cellular animal models suggested molecular mechanisms which mediate them. second part recent apoE4-targeted (from APOE gene to apoE protein its interactors) approaches have been are ready translated human. Further, issue whether due loss protective function gain toxic discussed herein. It both coexist, certain constituents molecule and/or downstream signaling mediating effect, while others associated function. ApoE4 promising target remains understudied. Recent now paving way effective apoE4-directed approaches.

Language: Английский

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Practical considerations for choosing a mouse model of Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2017, Volume and Issue: 12(1)

Published: Dec. 1, 2017

Alzheimer's disease (AD) is behaviorally identified by progressive memory impairment and pathologically characterized the triad of β-amyloid plaques, neurofibrillary tangles, neurodegeneration. Genetic mutations risk factors have been that are either causal or modify progression. These genetic pathological features serve as basis for creation validation mouse models AD. Efforts made in past quarter-century produced over 100 genetically engineered lines recapitulate some aspects AD clinicopathology. valuable resources understanding interactions contribute to cellular reactions engaged response. Here we focus on widely used stalwarts field recently developed bellwethers future. Rather than providing a summary each model, endeavor compare contrast approaches employed discuss their respective advantages limitations. We offer critical account variables which may inconsistent findings should be considered when choosing model interpreting results. hope present an insightful review current provide practical guide selecting best matched experimental question at hand.

Language: Английский

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Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: June 30, 2023

Abstract Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as molecular driver pathogenesis progression. Aβ prime target for development AD therapy. However, repeated failures Aβ-targeted clinical trials have cast considerable doubt on amyloid cascade hypothesis whether drug followed correct course. recent successes targeted assuaged those doubts. In this review, we discussed evolution over last 30 years summarized application diagnosis modification. particular, extensively pitfalls, promises important unanswered questions regarding current anti-Aβ therapy, well strategies further study more feasible approaches optimization prevention treatment.

Language: Английский

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Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease

Nature Neuroscience, Journal Year: 2021, Volume and Issue: 24(2), P. 276 - 287

Published: Jan. 11, 2021

Language: Английский

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The Amyloid Cascade Hypothesis in Alzheimer’s Disease: It’s Time to Change Our Mind

Current Neuropharmacology, Journal Year: 2017, Volume and Issue: 15(6)

Published: July 31, 2017

Since its discovery in 1984, the beta amyloid peptide has treaded boards of neurosciences as star molecule Alzheimer’s disease pathogenesis. In last decade, however, this vision been challenged by evidence-based medicine showing almost complete failure clinical trials that experimented anti-amyloid therapies with great hopes. Moreover, data have accumulated which clearly indicate small plays a key role physiological processes memory formation. present review, we will discuss different aspects cascade hypothesis, highlighting pros and cons, analyse results therapeutic approaches attempted to date should change direction research future. Keywords: Alzheimer's disease, amyloid, trials, LTP, memory, therapy.

Language: Английский

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Building Models of Brain Disorders with Three-Dimensional Organoids

Neuron, Journal Year: 2018, Volume and Issue: 100(2), P. 389 - 405

Published: Oct. 1, 2018

Language: Английский

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Chiral gold nanoparticles enantioselectively rescue memory deficits in a mouse model of Alzheimer’s disease

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Sept. 22, 2020

Abstract Preventing aggregation of amyloid beta (Aβ) peptides is a promising strategy for the treatment Alzheimer’s disease (AD), and gold nanoparticles have previously been explored as potential anti-Aβ therapeutics. Here we design prepare 3.3 nm L- D-glutathione stabilized (denoted L3.3 D3.3, respectively). Both chiral are able to inhibit Aβ42 cross blood-brain barrier (BBB) following intravenous administration without noticeable toxicity. D3.3 possesses larger binding affinity higher brain biodistribution compared with its enantiomer L3.3, giving rise stronger inhibition fibrillation better rescue behavioral impairments in AD model mice. This conjugation small nanoparticle recognition moiety provides therapeutic approach AD.

Language: Английский

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Phosphorylated tau interactome in the human Alzheimer’s disease brain

Brain, Journal Year: 2020, Volume and Issue: 143(9), P. 2803 - 2817

Published: June 23, 2020

Accumulation of phosphorylated tau is a key pathological feature Alzheimer's disease. Phosphorylated accumulation causes synaptic impairment, neuronal dysfunction and formation neurofibrillary tangles. The actions are mediated by surrounding proteins; however, comprehensive understanding the proteins that interacts with in disease surprisingly limited. Therefore, aim this study was to determine interactome. To end, we used two complementary proteomics approaches: (i) quantitative performed on tangles microdissected from patients advanced disease; (ii) affinity purification-mass spectrometry identify which these specifically bound tau. We identified 542 This included abundant detection many known be present such as tau, ubiquitin, neurofilament apolipoprotein E. Affinity confirmed 75 interacted PHF1-immunoreactive Twenty-nine have been previously associated therefore validating our proteomic approach. More importantly, 34 had total but not yet linked directly (e.g. protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, provide new evidence they interact In addition, also 12 novel proteins, physiologically or pathologically RNA binding HNRNPA1). Network analysis showed interactome enriched involved ubiquitination pathway phagosome maturation. Importantly, were able pinpoint specific pathways for first time, providing potential pathogenic mechanisms can explored future studies. Combined, results reveal drug targets treatment tauopathies insight into how mediates its toxicity

Language: Английский

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