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Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model

Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
Neurobiology of Disease (Impact Factor: 5.2). 12/2008; 33(2):229-35. DOI: 10.1016/j.nbd.2008.10.006
Source: PubMed

ABSTRACT Although animal models of Alzheimer's disease (AD) recapitulate beta-amyloid-dependent hippocampal synaptic and cognitive dysfunctions, it is poorly understood how cortex-dependent remote memory stabilization following initial hippocampal coding is affected. Here, we systematically analyzed biophysical and behavioral phenotypes, including remote memory functions, of 5XFAD APP/PS1 transgenic mice containing five familial AD mutations. We found that 5XFAD mice show hippocampal dysfunctions as observed by reduced levels of baseline transmission and long-term potentiation at Schaffer collateral-CA1 synapses. Hippocampus-dependent memory tested 1 day after contextual fear conditioning was also impaired age-dependently in 5XFAD mice, as correlated with the onset of hippocampal synaptic failures. Importantly, remote memory stabilization during 30 days after training significantly declined in 5XFAD mice at time well before the onset of hippocampal dysfunctions. Our results indicate that 5XFAD mice provide a useful model system to investigate the mechanisms and therapeutic interventions for multiple synaptic and memory dysfunctions associated with AD.

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    • "We previously surmised that the MSBs involving nonperforated synapses are particularly important for circuit plasticity, whereas those involving only perforated synapses may represent stable and strong connections (Nicholson and Geinisman 2009; see also Harris 1995; Woolley et al. 1996; Reilly et al. 2011). It is of interest, then, given their impairments in synaptic and behavioral plasticity (Oakley et al. 2006; Kimura and Ohno 2009; Kimuro et al. 2010; Crouzin et al. 2013), that the MSBs involving nonperforated synapses are the only ones that are reduced in number in the 5xADTg mice. In future experiments , it will be of interest to determine whether slicinginduced recuperative synaptogenesis (Kirov et al. 1999, 2004; Sorra et al. 2006) is different in WT and 5XADTg mice, given the loss of MSBs in perfusion-fixed hippocampus reported here. "
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    ABSTRACT: Alzheimer's disease (AD) is associated with alterations in the distribution, number, and size of inputs to hippocampal neurons. Some of these changes are thought to be neurodegenerative, whereas others are conceptualized as compensatory, plasticity-like responses, wherein the remaining inputs reactively innervate vulnerable dendritic regions. Here, we provide evidence that the axospinous synapses of human AD cases and mice harboring AD-linked genetic mutations (the 5XFAD line) exhibit both, in the form of synapse loss and compensatory changes in the synapses that remain. Using array tomography, quantitative conventional electron microscopy, immunogold electron microscopy for AMPARs, and whole-cell patch-clamp physiology, we find that hippocampal CA1 pyramidal neurons in transgenic mice are host to an age-related synapse loss in their distal dendrites, and that the remaining synapses express more AMPA-type glutamate receptors. Moreover, the number of axonal boutons that synapse with multiple spines is significantly reduced in the transgenic mice. Through serial section electron microscopic analyses of human hippocampal tissue, we further show that putative compensatory changes in synapse strength are also detectable in axospinous synapses of proximal and distal dendrites in human AD cases, and that their multiple synapse boutons may be more powerful than those in non-cognitively impaired human cases. Such findings are consistent with the notion that the pathophysiology of AD is a multivariate product of both neurodegenerative and neuroplastic processes, which may produce adaptive and/or maladaptive responses in hippocampal synaptic strength and plasticity.
    Brain Structure and Function 07/2014; DOI:10.1007/s00429-014-0848-z · 4.57 Impact Factor
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    • "We previously showed that excessive GluA1 Ser845 dephosphorylation in the 5XFAD hippocampus , associated with decreased surface levels of AMPARs, is attenuated in 5XFAD;Dp35KI compound mice (Figure 5E); thus, it is possible that other factors may underlie impaired basal synaptic transmission in the 5XFAD mice in a p25-independent manner. However, we found that the impaired LTP that is characteristic of the 5XFAD hippocampus (Chen et al., 2012; Kimura and Ohno, 2009) was restored to WT levels in the 5XFAD;Dp35KI compound mice (Figure 6A). Similarly, in behavioral experiments , we found that the established 5XFAD phenotypes of reduced anxiety (Jawhar et al., 2012) and poor cognitive performance in the novel-object recognition and contextual and cued FC paradigms were all suppressed in 5XFAD;Dp35KI compound mice (Figures 6B and 6C, and S6C). "
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    ABSTRACT: Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Δp35KI) to prevent p25 generation. The Δp35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Δp35KI mice with the 5XFAD mouse model of Alzheimer's disease (AD) resulted in an amelioration of β-amyloid (Aβ)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in Aβ-associated neurotoxicity and AD-like pathology.
    Cell 04/2014; 157(2):486-98. DOI:10.1016/j.cell.2014.01.065 · 33.12 Impact Factor
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    • "5XFAD mice, combining the APP/PS1 double transgenic mice with FAD mutations in APP (K670N/M671L, I716V, V717I) and in presenilin-1 (M146L, L286V), exhibit massive accumulation of cerebral Ab42; this amyloid deposition and gliosis begins at 2 months, is progressive and leads to impaired memory performance in Y-maze tests (Oakley et al. 2006). 5XFAD mice also show a reduction in baseline transmission levels and long-term potentiation at Schaffer collateral-CA1 synapses, which leads to hippocampal dysfunctions (Kimura and Ohno 2009). "
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    Genes & genomics 08/2013; 35(4). DOI:10.1007/s13258-013-0116-2 · 0.57 Impact Factor
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