Cortical Synaptic Integration<i>In Vivo</i>Is Disrupted by Amyloid-β Plaques

Stern, Edward A.; Bacskai, Brian J.; Hickey, Gregory A.; Attenello, Frank J.; Lombardo, Julianne A.; Hyman, Bradley T.

doi:10.1523/jneurosci.0462-04.2004

Cited by 194 publications

(169 citation statements)

References 50 publications

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“…However, our results, as well as the results of other studies (Urbanc et al, 2002;Spires et al, 2005) suggest that β-amyloid deposition may be associated with sublethal neuronal damage (i.e., synapse loss). Also, intracellular recordings from pyramidal neurons in Tg2576 mice show that β-amyloid plaques are associated with defects in cortical synaptic integration (Stern et al, 2004) and morphological studies in Tg2576 mice show that β-amyloid plaques are related to decreases in dendritic spine density (Lanz et al, 2003;Moolman et al, 2004;Tsai et al, 2004;Spires et al, 2005). Finally, Urbanc et al (2002) found that thioflavin-S positive plaques (fibrillar plaques) are selectively neurotoxic.…”

Section: Discussionmentioning

confidence: 99%

“…Synapse loss induced by Aβ remains a likely basis for the behavioral deficits observed in Tg2576 mice, since Aβ has been shown to disrupt neuronal function (Stern et al, 2004) and decrease dendritic spine density (Knowles et al, 1998;Lanz et al, 2003;Moolman et al, 2004;Tsai et al, 2004;Spires et al, 2005). However, studies using synaptophysin immunohistochemical staining under light microscopy have not produced consistent findings of synapse loss in Tg2576 mice.…”

Section: Introductionmentioning

confidence: 99%

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Spatial relationship between synapse loss and β‐amyloid deposition in Tg2576 mice

Dong

Martin

Chambers

et al. 2006

J of Comparative Neurology

134

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Although there is evidence that β-amyloid impairs synaptic function, the relationship between β-amyloid and synapse loss is not well understood. In this study, we assessed synapse density within the hippocampus and the entorhinal cortex of Tg2576 mice at 6-18 months of age using stereological methods at both the light and electron microscope levels. Under light microscopy, we failed to find overall decreases in the density of synaptophysin-positive boutons in any brain areas selected, but bouton density was significantly decreased within 200 μm of compact β-amyloid plaques in the outer molecular layer of the dentate gyrus and layers II and III of the entorhinal cortex at 15-18 months of age in Tg 2576 mice. Under electron microscopy, we found overall decreases in synapse density in the outer molecular layer of the dentate gyrus at both 6-9 and 15-18 months of age, and in layers II and III of the entorhinal cortex at 15-18 months of age in Tg 2576 mice. However, we did not find overall changes in synapse density in the stratum radiatum of the CA1 subfield. Furthermore, in the two former brain areas, we found a correlation between lower synapse density and greater proximity to β-amyloid plaques. These results provide the first quantitative morphological evidence at the ultrastructure level of a spatial relationship between β-amyloid plaques and synapse loss within the hippocampus and the entorhinal cortex of Tg2576 mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spatial relationship between synapse loss and β‐amyloid deposition in Tg2576 mice

Dong

Martin

Chambers

et al. 2006

J of Comparative Neurology

134

View full text Add to dashboard Cite

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“…We focused our structural assessments on the hippocampal formation because these structures play a major role in learning and memory (Knowles, 1992;Bannerman et al, 2001) and is also a site for Ab deposition in AD patients (Probst et al, 1983;West et al, 2004) and in several transgenic mouse models of AD (Su and Ni, 1998;Reilly et al, 2003). Synapse loss induced by Ab remains a likely basis for the behavioral deficits observed in Tg2576 mice (Stern et al, 2004). Previously, we demonstrated spatial and temporal relationships between synapse loss and Ab deposition in the dentate gyrus of Tg2576 mice at 6-9 months of age .…”

Section: Introductionmentioning

confidence: 99%

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

Dong

Yuede

Coughlan

et al. 2008

Neuropsychopharmacol

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Memantine, an uncompetitive NMDA receptor antagonist used for the treatment of Alzheimer's disease (AD), has been hypothesized to have neuroprotective properties. However, the similarity of its mechanism of action to other NMDA receptor antagonists has led to concerns that it may also have neurotoxic effects. To assess both the neuroprotective and neurotoxic potential of memantine in a mouse model of AD (Tg2576 mice), we used quantitative light and electron microscopy to investigate the effects of long-term (6 months) administration of memantine (5, 10 and 20 mg/kg) on plaque deposition and neuronal morphology in the hippocampus and overlying cortex. A fear-conditioning paradigm was used to evaluate the behavioral consequences of any observed changes in structure. Administration of the two higher doses of memantine (10 and 20 mg/kg) was associated with a significant decrease in b-amyloid (Ab) plaque deposition, increases in synaptic density and the appearance of degenerating axons; the latter two effects were independent of genotype. Administration of the lowest dose of memantine (5 mg/kg) was associated with a significant decrease in Ab plaque deposition and a significant increase in synaptic density, but not a significant increase in degenerating axons. However, memantine did not significantly improve behavioral deficits associated with genotype in a fear-conditioning paradigm at any dose. These results suggest that chronic memantine administration may have both neuroprotective and neurotoxic effects in a mouse model of AD.

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“…38 Therefore, we investigated effective connectivity changes in patients with aMCI based on the activation patterns. We applied GCM to investigate how parietal activation increases were related to the recruitment of other areas, and thus to possible compensation or disconnection.…”

Section: Example Of Task Stimuli and Activation Patternsmentioning

confidence: 99%

Functional integration of parietal lobe activity in early Alzheimer's disease

Jacobs¹,

Boxtel²,

Heinecke³

et al. 2012

Klin Neurophysiol

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Objectives: Parietal lobe dysfunction is an important characteristic of early Alzheimer disease (AD). Functional studies have shown conflicting parietal activation patterns indicative of either compensatory or dysfunctional mechanisms. This study aimed at examining activation differences in early AD using a visuospatial task. We focused on functional characteristics of the parietal lobe and examined compensation or disconnection mechanisms by combining a fMRI task with effective connectivity measures from Granger causality mapping (GCM).Methods: Eighteen male patients with amnestic mild cognitive impairment (aMCI) and 18 male cognitively healthy older individuals were given a mental rotation task with different rotation angles.Results: There were no behavioral group differences on the fMRI task. Separate measurements at each angle revealed widespread activation group differences. More temporal and parietal activation in the higher angle condition was observed in patients with aMCI. The parametric modulation, which identifies regions associated with increasing angle, confirmed these results. The GCM showed increased connectivity within the parietal lobe and between parietal and temporal regions in patients with aMCI. Decreased connectivity was found between the inferior parietal lobule and posterior cingulate gyrus. Connectivity patterns correlated with memory performance scores in patients with aMCI.Conclusions: Our results demonstrate increased effective temporoparietal connectivity in patients with aMCI, while maintaining intact behavioral performance. This might be a compensational mechanism to counteract a parietal-posterior cingulate gyrus disconnection. These findings highlight the importance of connectivity changes in the pathophysiology of AD. In addition, effective connectivity may be a promising method for evaluating interventions aimed at the promotion of compensatory mechanisms. Neurology ® 2012;78:352-360 GLOSSARY AD ϭ Alzheimer disease; aMCI ϭ amnestic mild cognitive impairment; CDR ϭ Clinical Dementia Rating; CSTE ϭ Cluster-level Statistical Threshold Estimator; DMN ϭ default mode network; FA ϭ flip angle; FOV ϭ field of view; GCM ϭ Granger causality mapping; MCI ϭ mild cognitive impairment; MTL ϭ medial temporal lobe; MUMC؉ ϭ Memory Clinic of the Maastricht University Medical Center; ROI ϭ region of interest; RT ϭ reaction time; TE ϭ echo time; TR ϭ repetition time.Parietal lobe dysfunction in early Alzheimer disease (AD) has been shown abundantly in both postmortem 1,2 and neuroimaging 3,4 studies. fMRI studies in early AD have shown indications for either compensation or functional loss. [5][6][7][8] Compensatory mechanisms have been observed in medial temporal but also in parietal areas. 5,7,9 Early AD has been associated with a disconnection between lobes with increased intralobe connectivity, 10 although some studies have reported interlobe disconnection. 10,11 Compensation reflects increased activation in one or more regions in order to maintain behavioral performance, while disconn...

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Cortical Synaptic IntegrationIn VivoIs Disrupted by Amyloid-β Plaques

Cited by 194 publications

References 50 publications

Spatial relationship between synapse loss and β‐amyloid deposition in Tg2576 mice

Spatial relationship between synapse loss and β‐amyloid deposition in Tg2576 mice

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

Functional integration of parietal lobe activity in early Alzheimer's disease

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