Duyckaerts, C., Potier, M. C. & Delatour, B. Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol. 115, 5-38

Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de La Salpêtrière, 47 Boulevard de l'Hôpital, 75651, Paris Cedex 13, France.
Acta Neuropathologica (Impact Factor: 10.76). 02/2008; 115(1):5-38. DOI: 10.1007/s00401-007-0312-8
Source: PubMed


Animal models aim to replicate the symptoms, the lesions or the cause(s) of Alzheimer disease. Numerous mouse transgenic lines have now succeeded in partially reproducing its lesions: the extracellular deposits of Abeta peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of Abeta peptide, similar but not identical to the Abeta peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of Abeta, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in Abeta 42 levels, except for the Arctic mutation, which alters the Abeta sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no Abeta deposition in most mouse lines. Doubly (APP x mutated PS1) transgenic mice develop the lesions earlier. Transgenic mice in which BACE1 has been knocked out or overexpressed have been produced, as well as lines with altered expression of neprilysin, the main degrading enzyme of Abeta. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of Abeta in the cell body of the neurons, inflammation and gliosis, and the dendritic alterations. They have allowed some insight to be gained into the kinetics of the changes. The connection between the symptoms, the lesions and the increase in Abeta oligomers has been found to be difficult to unravel. Neurofibrillary tangles are only found in mouse lines that overexpress mutated tau or human tau on a murine tau -/- background. A triply transgenic model (mutated APP, PS1 and tau) recapitulates the alterations seen in AD but its physiological relevance may be discussed. A number of modulators of Abeta or of tau accumulation have been tested. A transgenic model may be analyzed at three levels at least (symptoms, lesions, cause of the disease), and a reading key is proposed to summarize this analysis.

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    • "For instance, the vast majority of the transgenic mouse models focus on either the amyloid pathology or the neurofibrillary tangle pathology alone and not both together which is more representative of the disease state [168]. Therefore, it is clear that such animal models cannot address all the aspects of the disease [169]. It is vital to understand the interaction between tau protein and amyloid peptide and their synergistic effect in the progression of neural and behavioral pathologies in transgenic animal models [170]. "
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    ABSTRACT: Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.
    No preview · Article · Sep 2015 · Journal of Alzheimer's disease: JAD
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    • "AD is characterized by severe neuronal loss; primarily located in the hippocampus and the entorhinal cortex (Querfurth and Laferla, 2010). More than 100 transgenic mouse models of AD are now available (Duyckaerts et al., 2008, see also Most involve the expression of mutated amyloid precursor protein (APP), presenilin 1 (PS1), PS2 and/or Tau, and they replicate some neuropathological features and functional alterations of AD as well as memory deficits (Gotz and Ittner, 2008). "
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    ABSTRACT: Astrocytes play crucial roles in the brain and are involved in the neuroinflammatory response. They become reactive in response to virtually all pathological situations in the brain such as axotomy, ischemia, infection, and neurodegenerative diseases (ND). Astrocyte reactivity was originally characterized by morphological changes (hypertrophy, remodeling of processes) and the overexpression of the intermediate filament glial fibrillary acidic protein (GFAP). However, it is unclear how the normal supportive functions of astrocytes are altered by their reactive state. In ND, in which neuronal dysfunction and astrocyte reactivity take place over several years or decades, the issue is even more complex and highly debated, with several conflicting reports published recently. In this review, we discuss studies addressing the contribution of reactive astrocytes to ND. We describe the molecular triggers leading to astrocyte reactivity during ND, examine how some key astrocyte functions may be enhanced or altered during the disease process, and discuss how astrocyte reactivity may globally affect ND progression. Finally we will consider the anticipated developments in this important field. With this review, we aim to show that the detailed study of reactive astrocytes may open new perspectives for ND.
    Full-text · Article · Aug 2015 · Frontiers in Cellular Neuroscience
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    • "These changes were all rescued by the haploinsufficiency of Tp53, the gene that encodes all p53 isoforms (Fig. 5A and B). APP 695/swe mice display defects in the postsynaptic component of long-term potentiation (reviewed in Duyckaerts et al. 2008). These defects were also rescued by the haploinsufficiency of Tp53 (Fig. 5C). "
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    ABSTRACT: p44 is a short isoform of the tumor suppressor protein p53 that is regulated in an age-dependent manner. When overexpressed in the mouse, it causes a progeroid phenotype that includes premature cognitive decline, synaptic defects, and hyperphosphorylation of tau. The hyperphosphorylation of tau has recently been linked to the ability of p44 to regulate transcription of relevant tau kinases. Here, we report that the amyloid precursor protein (APP) intracellular domain (AICD), which results from the processing of the APP, regulates translation of p44 through a cap-independent mechanism that requires direct binding to the second internal ribosome entry site (IRES) of the p53 mRNA. We also report that AICD associates with nucleolin, an already known IRES-specific trans-acting factor that binds with p53 IRES elements and regulates translation of p53 isoforms. The potential biological impact of our findings was assessed in a mouse model of Alzheimer's disease. In conclusion, our study reveals a novel aspect of AICD and p53/p44 biology and provides a possible molecular link between APP, p44, and tau. Copyright © 2015 Elsevier Inc. All rights reserved.
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