Activity-induced expression of Arc is necessary for maintenance of long-term potentiation and for memory consolidation. In transgenic (TG) mice with neuronal production of human amyloid precursor protein (hAPP) and hAPP-derived amyloid-beta (Abeta) peptides, basal Arc expression was reduced primarily in granule cells of the dentate gyrus. After exploration of a novel environment, Arc expression in these neurons was unaltered in hAPP mice but increased markedly in nontransgenic controls. Other TG neuronal populations showed no or only minor deficits in Arc expression, indicating a special vulnerability of dentate granule cells. The phosphorylation states of NR2B and ERK1/2 were reduced in the dentate gyrus of hAPP mice, suggesting attenuated activity in NMDA-dependent signaling pathways that regulate synaptic plasticity as well as Arc expression. Arc reductions in hAPP mice correlated with reductions in the actin-binding protein alpha-actinin-2, which is located in dendritic spines and, like Arc, fulfills important functions in excitatory synaptic activity. Reductions in Arc and alpha-actinin-2 correlated tightly with reductions in Fos and calbindin, shown previously to reflect learning deficits in hAPP mice. None of these alterations correlated with the extent of plaque formation, suggesting a plaque-independent mechanism of hAPP/Abeta-induced neuronal deficits. The brain region-specific depletion of factors that participate in activity-dependent modification of synapses may critically contribute to cognitive deficits in hAPP mice and possibly in humans with Alzheimer's disease.
"Among them, aberrant expression of the neuromodulator neuropeptide Y (NPY) and depletion of the activity-dependent protein calbindin D-28k (CB) are thought to reflect hippocampal modifications induced by Aβ/human Amyloid Precursor Protein (hAPP) toxicity and pathogenicity [6,7,9–11]. In several mouse models of AD, the expression of some of these functional markers was shown to correlate with each other and with the severity of learning and memory impairments [6,7,10]. It was hypothesized that these modifications of the hippocampal circuits may actively contribute to the observed behavioral deficits associated with AD pathology . "
[Show abstract][Hide abstract] ABSTRACT: At advanced stages of Alzheimer's disease, cognitive dysfunction is accompanied by severe alterations of hippocampal circuits that may largely underlie memory impairments. However, it is likely that anatomical remodeling in the hippocampus may start long before any cognitive alteration is detected. Using the well-described Tg2576 mouse model of Alzheimer's disease that develops progressive age-dependent amyloidosis and cognitive deficits, we examined whether specific stages of the disease were associated with the expression of anatomical markers of hippocampal dysfunction. We found that these mice develop a complex pattern of changes in their dentate gyrus with aging. Those include aberrant expression of neuropeptide Y and reduced levels of calbindin, reflecting a profound remodeling of inhibitory and excitatory circuits in the dentate gyrus. Preceding these changes, we identified severe alterations of adult hippocampal neurogenesis in Tg2576 mice. We gathered converging data in Tg2576 mice at young age, indicating impaired maturation of new neurons that may compromise their functional integration into hippocampal circuits. Thus, disruption of adult hippocampal neurogenesis occurred before network remodeling in this mouse model and therefore may account as an early event in the etiology of Alzheimer's pathology. Ultimately, both events may constitute key components of hippocampal dysfunction and associated cognitive deficits occurring in Alzheimer's disease.
PLoS ONE 09/2013; 8(9):e76497. DOI:10.1371/journal.pone.0076497 · 3.23 Impact Factor
"Some of these mechanisms include inhibitory compensations to counteract the imbalance in excitatory function. There are structural changes that specifically remodel dentate gyrus, such as the sprouting of neuropeptide-Y (NPY)-inhibitory terminals onto granule cells (Palop et al., 2007), reduced expression of Arc and ␣-actinin-2 (Palop et al., 2005), reduced calcium-binding protein calbindin (CB) in CB-interneurons and c-Fos (Palop et al., 2003), plus the reduced phosphorylation states in NR2B and ERK1/2, many of them reducing the activity in plasticity dependent NMDA-signaling pathway in this hippocampal region (Palop et al., 2005). All of these compensatory mechanisms tend to increase inhibition or decrease excitation, which might interfere with normal network processing and can contribute to the AD phenotype (Palop et al., 2007; Palop and Mucke, 2009). "
[Show abstract][Hide abstract] ABSTRACT: Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulates the function of the adult nervous system. In fact, most of the key components including Wnts and Frizzled receptors are expressed in the adult brain. Wnt ligands have been implicated in the regulation of synaptic assembly as well as in neurotransmission and synaptic plasticity. Deregulation of Wnt signaling has been associated with several pathologies, and more recently has been related to neurodegenerative diseases and to mental and mood disorders. In this review, we focus our attention on the Wnt signaling cascade in postnatal life and we review in detail the presence of Wnt signaling components in pre- and postsynaptic regions. Due to the important role of Wnt proteins in wiring neural circuits, we discuss recent findings about the role of Wnt pathways both in basal spontaneous activities as well as in activity-dependent processes that underlie synaptic plasticity. Finally, we review the the role of Wnt in vivo and we finish with the most recent data in literature that involves the effect of components of the Wnt signaling pathway in neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling, as well as the data that support a neuroprotective role of Wnt proteins in relation to the pathogenesis of Alzheimer's disease.
Ageing research reviews 05/2013; 12(3). DOI:10.1016/j.arr.2013.03.006 · 4.94 Impact Factor
"We found that chronic B1R antagonism improved spatial learning and memory in APP mice, abilities that depend largely on hippocampal integrity . Moreover, prolonged B1R blockade enhanced the baseline levels of the memory-related Egr-1 protein in the DG, a brain region previously associated in APP mice with cognitive deficits, reduced immediate-early gene expression and altered synaptic activity [57,58]. Although further experiments would be required to confirm this hypothesis, it is conceivable that under chronic B1R blockade with SSR240612 in APP mice, BK can then act on its normal target and preferentially activate constitutive B2R that are considered neuroprotective and able to prevent memory loss . "
[Show abstract][Hide abstract] ABSTRACT: Background
Recent evidence suggests that the inducible kinin B1 receptor (B1R) contributes to pathogenic neuroinflammation induced by amyloid-beta (Aβ) peptide. The present study aims at identifying the cellular distribution and potentially detrimental role of B1R on cognitive and cerebrovascular functions in a mouse model of Alzheimer’s disease (AD).
Transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APPSwe,Ind, line J20) were treated with a selective and brain penetrant B1R antagonist (SSR240612, 10 mg/kg/day for 5 or 10 weeks) or vehicle. The impact of B1R blockade was measured on i) spatial learning and memory performance in the Morris water maze, ii) cerebral blood flow (CBF) responses to sensory stimulation using laser Doppler flowmetry, and iii) reactivity of isolated cerebral arteries using online videomicroscopy. Aβ burden was quantified by ELISA and immunostaining, while other AD landmarks were measured by western blot and immunohistochemistry.
B1R protein levels were increased in APP mouse hippocampus and, prominently, in reactive astrocytes surrounding Aβ plaques. In APP mice, B1R antagonism with SSR240612 improved spatial learning, memory and normalized protein levels of the memory-related early gene Egr-1 in the dentate gyrus of the hippocampus. B1R antagonism restored sensory-evoked CBF responses, endothelium-dependent dilations, and normalized cerebrovascular protein levels of endothelial nitric oxide synthase and B2R. In addition, SSR240612 reduced (approximately 50%) microglial, but not astroglial, activation, brain levels of soluble Aβ1-42, diffuse and dense-core Aβ plaques, and it increased protein levels of the Aβ brain efflux transporter lipoprotein receptor-related protein-1 in cerebral microvessels.
These findings show a selective upregulation of astroglial B1R in the APP mouse brain, and the capacity of the B1R antagonist to abrogate amyloidosis, cerebrovascular and memory deficits. Collectively, these findings provide convincing evidence for a role of B1R in AD pathogenesis.
Journal of Neuroinflammation 05/2013; 10(1):57. DOI:10.1186/1742-2094-10-57 · 5.41 Impact Factor
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