+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


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

          Related collections

          Most cited references154

          • Record: found
          • Abstract: found
          • Article: not found

          A specific amyloid-beta protein assembly in the brain impairs memory.

          Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice ( 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.
            • Record: found
            • Abstract: found
            • Article: not found

            Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.

            Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.
              • Record: found
              • Abstract: found
              • Article: not found

              ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

              APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.

                Author and article information

                (713) 798-8337 , jankowsk@bcm.edu
                (713) 798-5804 , huiz@bcm.edu
                Mol Neurodegener
                Mol Neurodegener
                Molecular Neurodegeneration
                BioMed Central (London )
                22 December 2017
                22 December 2017
                : 12
                [1 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Neuroscience, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [2 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Neurology, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [3 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Neurosurgery, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [4 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Molecular and Cellular Biology, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [5 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Huffington Center on Aging, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [6 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Molecular and Human Genetics, , Baylor College of Medicine, ; Houston, TX 77030 USA
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;
                Award ID: AG058188
                Award ID: AG056028
                Award ID: AG054160
                Award ID: AG020670
                Award ID: AG032051
                Award ID: AG054111
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;
                Award ID: NS092615
                Award ID: NS093652
                Award Recipient :
                Custom metadata
                © The Author(s) 2017

                transgenic mouse,knockout,knock-in,amyloid precursor protein,app,,tau,mapt,trem2,apolipoprotein e,apoe
                transgenic mouse, knockout, knock-in, amyloid precursor protein, app, , tau, mapt, trem2, apolipoprotein e, apoe


                Comment on this article