scholarly journals E22Δ Mutation in Amyloidβ-Protein Promotesβ-Sheet Transformation, Radical Production, and Synaptotoxicity, But Not Neurotoxicity

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Takayuki Suzuki ◽  
Kazuma Murakami ◽  
Naotaka Izuo ◽  
Toshiaki Kume ◽  
Akinori Akaike ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Conformational Change ◽  
Deletion Mutant ◽  
Protein A ◽  
Type A ◽  
Synaptic Dysfunction ◽  
Wild Type ◽  
Radical Production

Oligomers of 40- or 42-mer amyloidβ-protein (Aβ40, Aβ42) cause cognitive decline and synaptic dysfunction in Alzheimer's disease. We proposed the importance of a turn at Glu22 and Asp23 of Aβ42 to induce its neurotoxicity through the formation of radicals. Recently, a novel deletion mutant at Glu22 (E22Δ) of Aβ42 was reported to accelerate oligomerization and synaptotoxicity. To investigate this mechanism, the effects of the E22Δ mutation in Aβ42 and Aβ40 on the transformation ofβ-sheets, radical production, and neurotoxicity were examined. Both mutants promotedβ-sheet transformation and the formation of radicals, while their neurotoxicity was negative. In contrast, E22P-Aβ42 with a turn at Glu22 and Asp23 exhibited potent neurotoxicity along with the ability to form radicals and potent synaptotoxicity. These data suggest that conformational change in E22Δ-Aβis similar to that in E22P-Aβ42 but not the same, since E22Δ-Aβ42 exhibited no cytotoxicity, unlike E22P-Aβ42 and wild-type Aβ42.

Preclinical Alzheimer's disease

2014 ◽  
Vol 24 (2) ◽  
pp. 117-121
Author(s):  
P Gil-Gregorio ◽  
R Yubero-Pancorbo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Diagnostic Criteria ◽  
Stage I ◽  
Disease Stage ◽  
Synaptic Dysfunction ◽  
Preclinical Alzheimer’S Disease ◽  
Cerebral Amyloidosis ◽  
Three Stages

SummaryRecently, diagnostic criteria for preclinical Alzheimer's disease have been proposed. These describe and define three stages of disease. Stage I is focused on asymptomatic cerebral amyloidosis. Stage II includes evidence of synaptic dysfunction and/or early degeneration. Finally, stage III of the disease is characterized by the beginning of cognitive decline.

scholarly journals A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer’s Disease

2020 ◽  
Author(s):  
Natalie Ness ◽  
Simon R. Schultz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Neuronal Network ◽  
Cell Function ◽  
Place Cell ◽  
Transformation Model ◽  
Synaptic Dysfunction ◽  
Synapse Loss

AbstractAlzheimer’s Disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. Synaptic dysfunction is an established early symptom, which correlates strongly with cognitive decline, and is hypothesised to mediate the diverse neuronal network abnormalities observed in AD. However, how synaptic dysfunction contributes to network pathology and cognitive impairment in AD remains elusive. Here, we present a grid-cell-to-place-cell transformation model of long-term CA1 place cell dynamics to interrogate the effect of synaptic loss on network function and environmental representation. Synapse loss modelled after experimental observations in the APP/PS1 mouse model was found to induce firing rate alterations and place cell abnormalities that have previously been observed in AD mouse models, including enlarged place fields and lower across-session stability of place fields. Our results support the hypothesis that synaptic dysfunction underlies cognitive deficits, and demonstrate how impaired environmental representation may arise in the early stages of AD. We further propose that dysfunction of excitatory and inhibitory inputs to CA1 pyramidal cells may cause distinct impairments in place cell function, namely reduced stability and place map resolution.Author SummaryCognitive decline in Alzheimer’s Disease (AD) correlates most strongly with dysfunction and loss of synapses in affected brain regions. While synaptic dysfunction is a well-established early symptom of AD, how impaired synaptic transmission may lead to progressive cognitive decline, remains subject to active research. In this study, we examine the effect of synapse loss on neuronal network function using a computational model of place cells in the hippocampal network. Place cells encode a cognitive map of an animal’s environment, enabling navigation and spatial memory. This provides a useful indicator of cognitive function, as place cell function is well characterized and abnormalities in place cell firing have been shown to underlie navigational deficits in rodents. We find that synapse loss in our network is sufficient to produce progressive impairments in place cell function, which resemble those observed in mouse models of the disease, supporting the hypothesis that synaptic dysfunction may underlie the cognitive impairment in AD. Furthermore, we observe that loss of excitatory and inhibitory synapses produce distinct spatial impairments. Future experiments investigating the relative contribution of different synaptic inputs may thus allow new insights into the neuronal network alterations in AD and potentially enable the identification of new therapeutic targets.

Abstract TMP114: Cerebral Ischemia Combined With Amyloid Angiopathy Significantly Deteriorated Cognitive Impairment via Angiotensin AT1 Receptor in a Mouse Model of Alzheimer’s Disease

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Takashi Nakagawa ◽  
Yu Hasegawa ◽  
Shokei K Mitsuyama
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cerebral Ischemia ◽  
Cognitive Decline ◽  
Escape Latency ◽  
Amyloid Angiopathy ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mouse

Introduction: Ischemic stroke is suggested to be potentially associated with cognitive impairment in Alzheimer’s disease. Recent clinical data suggest that treatment with angiotensin receptor blocker (ARB) is associated with less incidence of Alzheimer’s disease than other classes of antihypertensive drugs. However, it is unknown whether cerebral ischemia can indeed trigger cognitive decline in Alzheimer’s disease and whether ARB can exert beneficial effect on ischemia-induced cognitive decline. Hypothesis: We hypothesized that cerebral ischemia deteriorates cognitive impairment in Alzheimer’s disease, through angiotensin II. Methods and results: We used 5XFAD mouse, a model of Alzheimer’s disease with vascular and cerebral amyloid-β(Aβ) deposition. Transient cerebral ischemia of mice was induced by bilateral common carotid artery occlusion (BCCAO) for 17 minutes. The post-treatment with olmesartan, an ARB, or vehicle was started at 24 hours after BCCAO, and was performed for 5 weeks. Mice were divided into 5 groups: (1) wild type, (2) wild type with BCCAO, (3) 5XFAD, (4) 5XFAD with BCCAO, (5) 5XFAD with BCCAO and olmesartan administration, to evaluate cognitive impairment. BCCAO in 5XFAD caused greater escape latency (p<0.01) on Water maze test (reference-/working-memory) and greater migration distance (p<0.05) on Open field test than that in wild type, indicating that cerebral ischemia combined with Aβ deposition enhanced cognitive decline. Post-treatment with olmesartan significantly reduced escape latency (p<0.01) on Water maze test, retention trial latency (p<0.05) on Passive avoidance test, and retention time of outer zone (p<0.01) on Open field test in 5XFAD subjected to BCCAO. BCCAO significantly deteriorated cognitive impairment, and this protection against BCCAO by olmesartan was associated with the protection of neuron in hippocampus and the suppression of blood-brain barrier disruption. Furthermore, olmesartan significantly attenuated brain oxidative stress, and NADPH oxidase subunits P67 in 5XFAD. Conclusion: We first demonstrated that cerebral ischemia combined with amyloid angiopathy markedly deteriorates cognitive impairment in 5XFAD mouse, through AT1 receptor.

Proteolytic processing of the amyloid-beta protein precursor of Alzheimer's disease

2002 ◽  
Vol 38 ◽  
pp. 37-49 ◽  
Author(s):  
Janelle Nunan ◽  
David H Small
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Alternative Pathway ◽  
Protein A ◽  
Proteolytic Processing ◽  
Gamma Secretase ◽  
Amyloid Beta Protein ◽  
Protein Precursor ◽  
Amyloid Beta Protein Precursor

The proteolytic processing of the amyloid-beta protein precursor plays a key role in the development of Alzheimer's disease. Cleavage of the amyloid-beta protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving beta- and gamma-secretase, liberates amyloid-beta protein, a protein associated with the neurodegeneration seen in Alzheimer's disease. The alternative pathway, involving alpha-secretase, precludes amyloid-beta protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer's disease.

[18F]-florbetaben PET/CT Imaging in the Alzheimer’s Disease Mouse Model APPswe/PS1dE9

2018 ◽  
Vol 16 (1) ◽  
pp. 49-55 ◽  
Author(s):  
J. Stenzel ◽  
C. Rühlmann ◽  
T. Lindner ◽  
S. Polei ◽  
S. Teipel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
New Drugs ◽  
Imaging Data ◽  
Wild Type ◽  
Preclinical Research ◽  
Standardized Uptake Values ◽  
Pet Ct

Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer’s disease (AD). In preclinical research, [<sup>18</sup>F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [<sup>18</sup>F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques. Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [<sup>18</sup>F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [<sup>18</sup>F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed. Results: Visual inspection and SUVs revealed an increased cerebral uptake of [<sup>18</sup>F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [<sup>18</sup>F]-florbetaben in the APPswe/PS1dE9 mouse model.

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