Kimura R, Ohno M. Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol Dis 33: 229-235

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: 5.08). 12/2008; 33(2):229-35. DOI: 10.1016/j.nbd.2008.10.006
Source: PubMed


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.

26 Reads
  • Source
    • "Early accumulation (2–4 months) of Aβ 3-42 pyroglutamate, a highly toxic species of Aβ, and axonal swelling have also been reported in the hippocampus of 5xFAD mice (Jawhar et al., 2012; Moon et al., 2012). Together, these data highlight the interest of studying the physiopathology of the hippocampus in the 5xFAD mouse model, and provide further molecular support for the impairment of hippocampal synaptic transmission reported in 5xFAD mice (Kimura and Ohno, 2009; Crouzin et al., 2013). Our study provides the first evidence that different MMPs involved in APP/Aβ metabolism are differentially regulated in a spatio-temporal manner in the 5xFAD murine model of AD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Matrix metalloproteinases (MMPs) are pleiotropic endopeptidases involved in a variety of neurodegenerative/neuroinflammatory processes through their interactions with a large number of substrates. Among those, the amyloid precursor protein (APP) and the beta amyloid peptide (Aβ) are largely associated with the development of Alzheimer's disease (AD). However, the regulation and potential contribution of MMPs to AD remains unclear. In this study, we investigated the evolution of the expression of MMP-2, MMP-9, and membrane-type 1-MMP (MT1-MMP) in the hippocampus at different stages of the pathology (asymptomatic, prodromal-like and symptomatic) in the 5xFAD transgenic mouse AD model. In parallel we also followed the expression of functionally associated factors. Overall, the expression of MMP-2, MMP-9, and MT1-MMP was upregulated concomitantly with the tissue inhibitor of MMPs-1 (TIMP-1) and several markers of inflammatory/glial response. The three MMPs exhibited age-and cell-dependent upregulation of their expression, with MMP-2 and MMP-9 being primarily located to astrocytes, and MT1-MMP to neurons. MMP-9 and MT1-MMP were also prominently present in amyloid plaques. The levels of active MT1-MMP were highly upregulated in membrane-enriched fractions of hippocampus at 6 months of age (symptomatic phase), when the levels of APP, its metabolites APP C-terminal fragments (CTFs), and Aβ trimers were the highest. Overexpression of MT1-MMP in HEK cells carrying the human APP Swedish mutation (HEKswe) strongly increased β-secretase derived C-terminal APP fragment (C99) and Aβ levels, whereas MMP-2 overexpression nearly abolished Aβ production without affecting C99. Our data consolidate the emerging idea of a regulatory interplay between MMPs and the APP/Aβ system, and demonstrate for the first time the pro-amyloidogenic features of MT1-MMP. Further investigation will be justified to evaluate this MMP as a novel potential therapeutic target in AD.
    Full-text · Article · Sep 2014 · Frontiers in Aging Neuroscience
  • Source
    • "The Tg2576 model over-expressing mutated hAβPP resulting in AβPP metabolite pathology is uniquely suited to assessing early, pre-depositing stages of pathology due to its relatively late onset of Aβ plaque deposition [23]. Compared to more aggressive models such as the 5XFAD [24], [25] and TgCRND8 [26], [27] which begin to exhibit plaque formation at 3 and 5 months of age respectively, the Tg2576 do not show clear amyloid plaque accumulation in cortical areas until about 10–12 months of age [23], [28]. Therefore, we are able to investigate how olfactory performance correlates with single-unit processing of odor stimuli in the aPCX of the pre-depositing brain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease is a neurodegenerative disorder that is the most common cause of dementia in the elderly today. One of the earliest reported signs of Alzheimer's disease is olfactory dysfunction, which may manifest in a variety of ways. The present study sought to address this issue by investigating odor coding in the anterior piriform cortex, the primary cortical region involved in higher order olfactory function, and how it relates to performance on olfactory behavioral tasks. An olfactory habituation task was performed on cohorts of transgenic and age-matched wild-type mice at 3, 6 and 12 months of age. These animals were then anesthetized and acute, single-unit electrophysiology was performed in the anterior piriform cortex. In addition, in a separate group of animals, a longitudinal odor discrimination task was conducted from 3-12 months of age. Results showed that while odor habituation was impaired at all ages, Tg2576 performed comparably to age-matched wild-type mice on the olfactory discrimination task. The behavioral data mirrored intact anterior piriform cortex single-unit odor responses and receptive fields in Tg2576, which were comparable to wild-type at all age groups. The present results suggest that odor processing in the olfactory cortex and basic odor discrimination is especially robust in the face of amyloid β precursor protein (AβPP) over-expression and advancing amyloid β (Aβ) pathology. Odor identification deficits known to emerge early in Alzheimer's disease progression, therefore, may reflect impairments in linking the odor percept to associated labels in cortical regions upstream of the primary olfactory pathway, rather than in the basic odor processing itself.
    Full-text · Article · Sep 2014 · PLoS ONE
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jul 2014 · Brain Structure and Function
Show more

Full-text (3 Sources)

26 Reads
Available from
Feb 24, 2015