Reversible Pathologic and Cognitive Phenotypes in an Inducible Model of Alzheimer-Amyloidosis

Departments of Pathology and Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2013; 33(9):3765-79. DOI: 10.1523/JNEUROSCI.4251-12.2013
Source: PubMed


Transgenic mice that express mutant amyloid precursor protein (APPsi) using tet-Off vector systems provide an alternative model for assessing short- and long-term effects of Aβ-targeting therapies on phenotypes related to the deposition of Alzheimer-type amyloid. Here we use such a model, termed APPsi:tTA, to determine what phenotypes persist in mice with high amyloid burden after new production of APP/Aβ has been suppressed. We find that 12- to 13-month-old APPsi:tTA mice are impaired in cognitive tasks that assess short- and long-term memories. Acutely suppressing new APPsi/Aβ production produced highly significant improvements in performing short-term spatial memory tasks, which upon continued suppression translated to superior performance in more demanding tasks that assess long-term spatial memory and working memory. Deficits in episodic-like memory and cognitive flexibility, however, were more persistent. Arresting mutant APPsi production caused a rapid decline in the brain levels of soluble APP ectodomains, full-length APP, and APP C-terminal fragments. As expected, amyloid deposits persisted after new APP/Aβ production was inhibited, whereas, unexpectedly, we detected persistent pools of solubilizable, relatively mobile, Aβ42. Additionally, we observed persistent levels of Aβ-immunoreactive entities that were of a size consistent with SDS-resistant oligomeric assemblies. Thus, in this model with significant amyloid pathology, a rapid amelioration of cognitive deficits was observed despite persistent levels of oligomeric Aβ assemblies and low, but detectable solubilizable Aβ42 peptides. These findings implicate complex relationships between accumulating Aβ and activities of APP, soluble APP ectodomains, and/or APP C-terminal fragments in mediating cognitive deficits in this model of amyloidosis.

Full-text preview

Available from:
    • "ab , reported to target Ab aggregates , includ ing plaques , but sparing monomers ( Patel , 2015 ) . Never theless , other studies have revised the role of oligomers , finding that blocking new production of APP / Ab amelio rated the AD phenotype in animal models despite persis tent levels of previously formed soluble and insoluble Ab assemblies ( Melnikova et al . , 2013 ) . These controversial results might be understandable in light of the complexity of Ab aggregation and the continuous dynamic rearrangement of oligomers ( Bemporad and Chiti , 2012 ) . Ab is secreted in monomeric form and this has lead to ascribe the physiologic effects of Ab to monomers . However a certain degree of oligomer ization "
    [Show abstract] [Hide abstract]
    ABSTRACT: For several years Amyloid-beta peptide (Aβ) has been considered the main pathogenetic factor of Alzheimer's disease (AD). According to the so called Amyloid Cascade Hypothesis the increase of Aβ triggers a series of events leading to synaptic dysfunction and memory loss as well as to the structural brain damage in the later stage of the disease. However, several evidences suggest that this hypothesis is not sufficient to explain AD pathogenesis, especially considering that most of the clinical trials aimed to decrease Aβ levels have been unsuccessful. Moreover, Aβ is physiologically produced in the healthy brain during neuronal activity and it is needed for synaptic plasticity and memory. Here we propose a model interpreting AD pathogenesis as an alteration of the negative feedback loop between Aβ and its physiological receptors, focusing on α7-nAchRs. According to this vision, when Aβ cannot exert its physiological function a negative feedback mechanism would induce a compensatory increase of its production leading to an abnormal accumulation that reduces α7-nAchR function, leading to synaptic dysfunction and memory loss. In this perspective, the indiscriminate Aβ removal might worsen neuronal homeostasis, causing a further impoverishment of learning and memory. Even if further studies are needed to better understand and validate these mechanisms, we believe that to deepen the role of Aβ in physiological conditions might represent the keystone to elucidate important aspects of AD pathogenesis. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 08/2015; 307. DOI:10.1016/j.neuroscience.2015.08.039 · 3.36 Impact Factor
  • Source
    • "Primarily, they point to possible roles of full length APP or other APP derivatives in mediating Aβ-associated toxicity in mouse models. This hypothesis is supported by recent evidence demonstrating that conditional suppression of mutated human APP transgene at the stage of florid Aβ pathology in a mouse model restored learning propensity of the mice, despite the presence of abundant Aβ plaques in the brain [52]. Another possibility is that seemingly toxic Aβ oligomers may not be homogenous assemblies of Aβ, but may contain other APP derivatives that contribute to toxicity [53]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Recent research in Alzheimer’s disease (AD) field has been focused on the potential role of the amyloid-β protein that is derived from the transmembrane amyloid precursor protein (APP) in directly mediating cognitive impairment in AD. Transgenic mouse models overexpressing APP develop robust AD-like amyloid pathology in the brain and show various levels of cognitive decline. In the present study, we examined the cognition of the BRI2-Aβ transgenic mouse model in which secreted extracellular Aβ1-40, Aβ1-42 or both Aβ1-40/Aβ1-42 peptides are generated from the BRI-Aβ fusion proteins encoded by the transgenes. BRI2-Aβ mice produce high levels of Aβ peptides and BRI2-Aβ1-42 mice develop amyloid pathology that is similar to the pathology observed in mutant human APP transgenic models. Results Using established behavioral tests that reveal deficits in APP transgenic models, BRI2-Aβ1-42 mice showed completely intact cognitive performance at ages both pre and post amyloid plaque formation. BRI2-Aβ mice producing Aβ1-40 or both peptides were also cognitively intact. Conclusions These data indicate that high levels of Aβ1-40 or Aβ1-42, or both produced in the absence of APP overexpression do not reproduce memory deficits observed in APP transgenic mouse models. This outcome is supportive of recent data suggesting that APP processing derivatives or the overexpression of full length APP may contribute to cognitive decline in APP transgenic mouse models. Alternatively, Aβ aggregates may impact cognition by a mechanism that is not fully recapitulated in these BRI2-Aβ mouse models.
    Molecular Neurodegeneration 05/2013; 8(1):15. DOI:10.1186/1750-1326-8-15 · 6.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The data reported in the Technical Comments by Fitz et al., Price et al., Tesseur et al., and Veeraraghavalu et al. replicate and validate our central conclusion that bexarotene stimulates the clearance of soluble β-amyloid peptides and results in the reversal of behavioral deficits in mouse models of Alzheimer's disease (AD). The basis of the inability to reproduce the drug-stimulated microglial-mediated reduction in plaque burden is unexplained. However, we concluded that plaque burden is functionally unrelated to improved cognition and memory elicited by bexarotene.
    Science 05/2013; 340(6135):924. DOI:10.1126/science.1234114 · 33.61 Impact Factor
Show more