A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide

Sato, Kaori; Watamura, Naoto; Fujioka, Ryo; Mihira, Naomi; Sekiguchi, Masaki; Nagata, Kenichi; Ohshima, Toshio; Saito, Takashi; Saido, Takaomi C.; Sasaguri, Hiroki

doi:10.1016/j.jbc.2021.101004

Cited by 26 publications

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“…The App NL–F mice were crossed with Psen1 P 117 L mice, despite it being unclear whether their pathogenic effects, both of which act on the γ-cleavage of CTF-β, would be additive or not in vivo ( Figure 4 ). The pathological phenotypes of App NL–F mice were markedly enhanced in a synergistic manner with the Psen1 P 117 L mutation ( Sato et al, 2021 ), with App NL–F X Psen1 P 117 L/WT mice showing a more aggressive cored plaque pathology and neuroinflammation than the App NL–G–F mice ( Figure 5 ). These double mutant mice ( 3rd generation model ) will likely become highly relevant tools for examining the pathologic mechanisms upstream of Aβ deposition.…”

Section: St 2nd and 3rd Generation Mouse Models Of Alzheimer’s Diseasementioning

confidence: 99%

Recent Advances in the Modeling of Alzheimer’s Disease

et al. 2022

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Since 1995, more than 100 transgenic (Tg) mouse models of Alzheimer’s disease (AD) have been generated in which mutant amyloid precursor protein (APP) or APP/presenilin 1 (PS1) cDNA is overexpressed (1st generation models). Although many of these models successfully recapitulate major pathological hallmarks of the disease such as amyloid β peptide (Aβ) deposition and neuroinflammation, they have suffered from artificial phenotypes in the form of overproduced or mislocalized APP/PS1 and their functional fragments, as well as calpastatin deficiency-induced early lethality, calpain activation, neuronal cell death without tau pathology, endoplasmic reticulum stresses, and inflammasome involvement. Such artifacts bring two important uncertainties into play, these being (1) why the artifacts arise, and (2) how they affect the interpretation of experimental results. In addition, destruction of endogenous gene loci in some Tg lines by transgenes has been reported. To overcome these concerns, single App knock-in mouse models harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL–G–F and AppNL–F mice) were developed (2nd generation models). While these models are interesting given that they exhibit Aβ pathology, neuroinflammation, and cognitive impairment in an age-dependent manner, the model with the Artic mutation, which exhibits an extensive pathology as early as 6 months of age, is not suitable for investigating Aβ metabolism and clearance because the Aβ in this model is resistant to proteolytic degradation and is therefore prone to aggregation. Moreover, it cannot be used for preclinical immunotherapy studies owing to the discrete affinity it shows for anti-Aβ antibodies. The weakness of the latter model (without the Arctic mutation) is that the pathology may require up to 18 months before it becomes sufficiently apparent for experimental investigation. Nevertheless, this model was successfully applied to modulating Aβ pathology by genome editing, to revealing the differential roles of neprilysin and insulin-degrading enzyme in Aβ metabolism, and to identifying somatostatin receptor subtypes involved in Aβ degradation by neprilysin. In addition to discussing these issues, we also provide here a technical guide for the application of App knock-in mice to AD research. Subsequently, a new double knock-in line carrying the AppNL–F and Psen1P117L/WT mutations was generated, the pathogenic effect of which was found to be synergistic. A characteristic of this 3rd generation model is that it exhibits more cored plaque pathology and neuroinflammation than the AppNL–G–F line, and thus is more suitable for preclinical studies of disease-modifying medications targeting Aβ. Furthermore, a derivative AppG–F line devoid of Swedish mutations which can be utilized for preclinical studies of β-secretase modifier(s) was recently created. In addition, we introduce a new model of cerebral amyloid angiopathy that may be useful for analyzing amyloid-related imaging abnormalities that can be caused by anti-Aβ immunotherapy. Use of the App knock-in mice also led to identification of the α-endosulfine-KATP channel pathway as components of the somatostatin-evoked physiological mechanisms that reduce Aβ deposition via the activation of neprilysin. Such advances have provided new insights for the prevention and treatment of preclinical AD. Because tau pathology plays an essential role in AD pathogenesis, knock-in mice with human tau wherein the entire murine Mapt gene has been humanized were generated. Using these mice, the carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) was discovered as a mediator linking tau pathology to neurodegeneration and showed that tau humanization promoted pathological tau propagation. Finally, we describe and discuss the current status of mutant human tau knock-in mice and a non-human primate model of AD that we have successfully created.

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Section: St 2nd and 3rd Generation Mouse Models Of Alzheimer’s Diseasementioning

confidence: 99%

Recent Advances in the Modeling of Alzheimer’s Disease

et al. 2022

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“…Test dependency of genotype effects of App NL–G–F in behavioral tests has recently been emphasized ( Kundu et al, 2021 ). Meanwhile, the originators of the model have developed a 3rd generation AD mouse model, attempting to increase plaque pathology and neuroinflammation ( Sato et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…The App NL–G–F KI mice were suggested to exhibit 3-fold faster and greater AD pathology and cognitive abnormalities compared with App NL–F mice ( Sasaguri et al, 2017 ). The App NL–G–F KI mice were suggested to show extensive pathology as early as 6 months ( Mehla et al, 2019 ; Sato et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The Roles of Long-Term Hyperhomocysteinemia and Micronutrient Supplementation in the AppNL–G–F Model of Alzheimer’s Disease

Nieraad

Bruin

Arne

et al. 2022

Front. Aging Neurosci.

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A causal contribution of hyperhomocysteinemia to cognitive decline and Alzheimer’s disease (AD), as well as potential prevention or mitigation of the pathology by dietary intervention, have frequently been subjects of controversy. In the present in vivo study, we attempted to further elucidate the impact of elevated homocysteine (HCys) and homocysteic acid (HCA) levels, induced by dietary B-vitamin deficiency, and micronutrient supplementation on AD-like pathology, which was simulated using the amyloid-based AppNL–G–F knock-in mouse model. For this purpose, cognitive assessment was complemented by analyses of ex vivo parameters in whole blood, serum, CSF, and brain tissues from the mice. Furthermore, neurotoxicity of HCys and HCA was assessed in a separate in vitro assay. In confirmation of our previous study, older AppNL–G–F mice also exhibited subtle phenotypic impairment and extensive cerebral amyloidosis, whereas dietary manipulations did not result in significant effects. As revealed by proximity extension assay-based proteome analysis, the AppNL–G–F genotype led to an upregulation of AD-characteristic neuronal markers. Hyperhomocysteinemia, in contrast, indicated mainly vascular effects. Overall, since there was an absence of a distinct phenotype despite both a significant amyloid-β burden and serum HCys elevation, the results in this study did not corroborate the pathological role of amyloid-β according to the “amyloid hypothesis,” nor of hyperhomocysteinemia on cognitive performance. Nevertheless, this study aided in further characterizing the AppNL–G–F model and in elucidating the role of HCys in diverse biological processes. The idea of AD prevention with the investigated micronutrients, however, was not supported, at least in this mouse model of the disease.

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“…In conclusion, we emphasize that aging-associated down-regulation of NEP is likely a primary cause for SAD and that up-regulation of NEP expression or its activity in the CNS via somatostatin receptor activation should be considered as a strategy to reduce A deposition in preclinical AD to either halt or delay onset of the disease. Our 3 rd generation mouse model of AD that accumulates wild-type human A very rapidly 61 will become a powerful tool for the primary in vivo screening of such medication candidates.…”

Section: Discussionmentioning

confidence: 99%

Neprilysin-sensitive amyloidogenic Aβ versus IDE-sensitive soluble Aβ: a probable mechanistic cause for sporadic Alzheimer’s disease

Sasaguri

Takamura

Watamura

et al. 2021

Preprint

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Neprilysin (NEP) and insulin-degrading enzyme (IDE) are considered the two major catabolic enzymes that degrade amyloid beta peptide (Abeta), the primary cause of Alzheimer's disease (AD). However, their roles in Abeta metabolism in vivo have never been compared in an impartial and side-by-side manner. Here, we crossbred single App knock-in mice with NEP (Mme) KO mice and with IDE (Ide) KO mice to generate double mutants that were analyzed for their biochemical and Abeta pathology properties. We found that NEP is responsible for the metabolism of amyloidogenic insoluble Abeta whereas IDE affects soluble Abeta. A deficiency of NEP, but not of IDE, augmented the formation of Abeta plaques, dystrophic neurites, and astrocytic and microglial activation, all of which are key pathological events in the development of AD. In addition, a deficiency of NEP had no significant impact on the levels of various neuropeptides (somatostatin, substance P, cholecystokinin, and neuropeptide Y), well known to be in vitro substrates for NEP, presumably because NEP is expressed in secretory vesicles and on the presynaptic membranes of excitatory neurons while most if not all neuropeptides are secreted from inhibitory neurons. This argues against the concern that NEP up-regulation for treatment of preclinical AD would reduce the levels of these neuropeptides. These findings indicate that NEP relatively selectively degrades Abeta in the brain. Whereas familial AD (FAD) is unambiguously caused by an increased anabolism of Abeta, and of Abeta42 and Abeta43 in particular, the anabolism of Abeta appears unaffected before its deposition in the brain that subsequently leads to the onset of sporadic AD (SAD). These observations thus suggest that NEP-sensitive amyloidogenic Abeta likely plays a primary pathogenic role in the etiology of SAD. Our findings are consistent with the aging-dependent decline of NEP expression in human brain and with recent genome-wide association studies (GWAS) indicating that variants of the gene encoding NEP (MME) are associated with the risk of SAD development. Taken together, our results imply that the aging-associated decrease in NEP expression is a primary cause of SAD and could thus be a target for the treatment of preclinical AD once other factors such as apolipoprotein E genotypes have also been considered.

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A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide

Cited by 26 publications

References 50 publications

Recent Advances in the Modeling of Alzheimer’s Disease

Recent Advances in the Modeling of Alzheimer’s Disease

The Roles of Long-Term Hyperhomocysteinemia and Micronutrient Supplementation in the AppNL–G–F Model of Alzheimer’s Disease

Neprilysin-sensitive amyloidogenic Aβ versus IDE-sensitive soluble Aβ: a probable mechanistic cause for sporadic Alzheimer’s disease

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