scholarly journals Human brain-derived Aβ oligomers bind to synapses and disrupt synaptic activity in a manner that requires APP

2017 ◽  
Author(s):  
Zemin Wang ◽  
Rosemary J. Jackson ◽  
Wei Hong ◽  
Taylor M. Walter ◽  
Arturo Moreno ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glutamate Release ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
The United States ◽  
Synaptic Activity ◽  
Network Activity ◽  
Amyloid Β Protein ◽  
Genetic Ablation

AbstractCompelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer’s disease (AD), and several theories have been advanced to explain the involvement of APP in AD. A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid β-protein (Aβ), self-associates to form soluble aggregates which impair synaptic and network activity. Here, we report on the plasticity-disrupting effects of Aβ isolated from AD brain and the requirement of APP for these effects. We show that Aβ-containing AD brain extracts block hippocampal long-term potentiation (LTP), augment glutamate release probability and disrupt the excitation/inhibition balance. Notably, these effects are associated with Aβ localizing to synapses, and genetic ablation of APP prevents both Aβ binding and Aβ-mediated synaptic dysfunctions. These findings indicate a role for APP in AD pathogenesis beyond the generation of Aβ and suggest modulation of APP expression as a therapy for AD.AcknowledgmentsWe thank Dr. Tiernan T. O’Malley for useful discussions and technical advice. This work was supported by grants to DMW from the National Institutes of Health (AG046275), Bright Focus, and the United States-Israel Binational Science Foundation (2013244, DMW and IS); grants to TSJ from Alzheimer’s Research UK and the Scottish Government (ARUK-SPG2013-1), Wellcome Trust-University of Edinburgh Institutional Strategic Support funds, and the H2020 European Research Council (ALZSYN); and to the Massachusetts Alzheimer’s Disease Research Center (AG05134).

Inhalational Anesthetics Do Not Deteriorate Amyloid-β-Derived Pathophysiology in Alzheimer’s Disease: Investigations on the Molecular, Neuronal, and Behavioral Level

2021 ◽  
pp. 1-26
Author(s):  
Carolin Hofmann ◽  
Annika Sander ◽  
Xing Xing Wang ◽  
Martina Buerge ◽  
Bettina Jungwirth ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Performance ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Network Activity ◽  
Plaque Burden ◽  
Spine Density ◽  
General Anesthetics ◽  
Inhalational Anesthetics

Background: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer’s disease (AD) neuropathogenesis, e.g., increased amyloid-β (Aβ) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. Objective: In the present study, we want to detail the interactions of inhalational anesthetics with Aβ-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aβ oligomerization and Aβ-mediated neurotoxicity on processes related to cognition. Methods: Oligomerization of Aβ 1–42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and Aβ 1–42, Aβ 1–40, pyroglutamate-modified amyloid-(AβpE3), and nitrated Aβ (3NTyrAβ), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aβ plaque burden in transgenic AD mice (ArcAβ) after anesthesia. Results: Whereas isoflurane and sevoflurane did not affect Aβ 1–42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AβpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aβ 1–42-induced spine density attenuation. In the presence of Aβ 1–40 and AβpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aβ 1–42 or 3NTyrAβ, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAβ mice. Conclusion: None of the anesthetics aggravated Aβ-derived AD pathology in vivo. However, Aβ and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aβ 1–42 aggregation, LTP, and spine density.

scholarly journals New Alzheimer’s disease model mouse specialized for analyzing the function and toxicity of intraneuronal Amyloid β oligomers

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tomoyo Ochiishi ◽  
Masami Kaku ◽  
Kazuyuki Kiyosue ◽  
Motomichi Doi ◽  
Takao Urabe ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Model ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Amyloid Β Protein ◽  
Aβ Oligomers ◽  
Term Potentiation ◽  
Model Mouse

AbstractOligomers of intracellular amyloid β protein (Aβ) are strongly cytotoxic and play crucial roles in synaptic transmission and cognitive function in Alzheimer’s disease (AD). However, there is currently no AD model mouse in which to specifically analyze the function of Aβ oligomers only. We have now developed a novel AD model mouse, an Aβ-GFP transgenic mouse (Aβ-GFP Tg), that expresses the GFP-fused human Aβ1-42 protein, which forms only Aβ oligomers within neurons throughout their life. The fusion proteins are expressed mainly in the hippocampal CA1-CA2 region and cerebral cortex, and are not secreted extracellularly. The Aβ-GFP Tg mice exhibit increased tau phosphorylation, altered spine morphology, decreased expressions of the GluN2B receptor and neuroligin in synaptic regions, attenuated hippocampal long-term potentiation, and impaired object recognition memory compared with non-Tg littermates. Interestingly, these dysfunctions have already appeared in 2–3-months-old animals. The Aβ-GFP fusion protein is bioactive and highly toxic, and induces the similar synaptic dysfunctions as the naturally generated Aβ oligomer derived from postmortem AD patient brains and synthetic Aβ oligomers. Thus, Aβ-GFP Tg mouse is a new tool specialized to analyze the function of Aβ oligomers in vivo and to find subtle changes in synapses in early symptoms of AD.

The role of cell-derived oligomers of Aβ in Alzheimer's disease and avenues for therapeutic intervention

2005 ◽  
Vol 33 (5) ◽  
pp. 1087-1090 ◽  
Author(s):  
D.M. Walsh ◽  
I. Klyubin ◽  
G.M. Shankar ◽  
M. Townsend ◽  
J.V. Fadeeva ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Size Exclusion ◽  
Amyloid Β Protein ◽  
Aβ Oligomers ◽  
Aβ Peptides ◽  
Aβ Amyloid

Burgeoning evidence suggests that soluble oligomers of Aβ (amyloid β-protein) are the earliest effectors of synaptic compromise in Alzheimer's disease. Whereas most other investigators have employed synthetic Aβ peptides, we have taken advantage of a β-amyloid precursor protein-overexpressing cell line (referred to as 7PA2) that secretes sub-nanomolar levels of low-n oligomers of Aβ. These are composed of heterogeneous Aβ peptides that migrate on SDS/PAGE as dimers, trimers and tetramers. When injected into the lateral ventricle of rats in vivo, these soluble oligomers inhibit hippocampal long-term potentiation and alter the memory of a complex learned behaviour. Biochemical manipulation of 7PA2 medium including immunodepletion with Aβ-specific antibodies and fractionation by size-exclusion chromatography allowed us to unambiguously attribute these effects to low-n oligomers. Using this paradigm we have tested compounds directed at three prominent amyloid-based therapeutic targets: inhibition of the secretases responsible for Aβ production, inhibition of Aβ aggregation and immunization against Aβ. In each case, compounds capable of reducing oligomer production or antibodies that avidly bind Aβ oligomers also ameliorate the synaptotoxic effects of these natural, cell-derived oligomers.

Synaptic plasticity disruption by amyloid β protein: modulation by potential Alzheimer's disease modifying therapies

2005 ◽  
Vol 33 (4) ◽  
pp. 563-567 ◽  
Author(s):  
M.J. Rowan ◽  
I. Klyubin ◽  
Q. Wang ◽  
R. Anwyl
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Medial Temporal Lobe ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Soluble Form ◽  
Amyloid Β Protein ◽  
Aβ Oligomers ◽  
Aβ Amyloid

AD (Alzheimer's disease) is characterized by a progressive and devastating mental decline that is usually presaged by impairment of a form of memory dependent on medial temporal lobe structures, including the hippocampus. The severity of clinical dementia correlates positively with the cerebral load of the AD-related protein Aβ (amyloid β), particularly in its soluble form rather than the insoluble fibrillar Aβ found in amyloid plaques. Recent research in animal models of AD has pointed to a potentially important role for rapid disruptive effects of soluble species of Aβ on neural function in causing a relatively selective impairment of memory early in the disease. Our experiments assessing the mechanisms of Aβ inhibition of LTP (long-term potentiation), a correlate of memory-related synaptic plasticity, in the rodent hippocampus showed that low-n oligomers were the soluble Aβ species primarily responsible for the disruption of synaptic plasticity in vivo. Exogenously applied and endogenously generated anti-Aβ antibodies rapidly neutralized and prevented the synaptic plasticity disrupting effects of these very potent Aβ oligomers. This suggests that active or passive immunotherapeutic strategies for early AD should target Aβ oligomers in the brain. The ability of agents that reduce nitrosative/oxidative stress or antagonize stress-activated kinases to prevent Aβ inhibition of LTP in vitro points to a key role of these cellular mechanisms at very early stages in Aβ-induced neuronal dysfunction. A combination of antibody-mediated inactivation of Aβ oligomers and pharmacological prevention of cellular stress mechanisms underlying their synaptic plasticity disrupting effects provides an attractive strategy in the prevention of early AD.

scholarly journals Synaptic plasticity in animal models of early Alzheimer's disease

2003 ◽  
Vol 358 (1432) ◽  
pp. 821-828 ◽  
Author(s):  
Michael J. Rowan ◽  
Igor Klyubin ◽  
William K. Cullen ◽  
Roger Anwyl
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Active Species ◽  
Amyloid Β Protein ◽  
Early Alzheimer’S Disease

Amyloid β-protein (Aβ) is believed to be a primary cause of Alzheimer's disease (AD). Recent research has examined the potential importance of soluble species of Aβ in synaptic dysfunction, long before fibrillary Aβ is deposited and neurodegenerative changes occur. Hippocampal excitatory synaptic transmission and plasticity are disrupted in transgenic mice overexpressing human amyloid precursor protein with early onset familial AD mutations, and in rats after exogenous application of synthetic Aβ both in vitro and in vivo . Recently, naturally produced soluble Aβ was shown to block the persistence of long-term potentiation (LTP) in the intact hippocampus. Sub-nanomolar concentrations of oligomeric Aβ were sufficient to inhibit late LTP, pointing to a possible reason for the sensitivity of hippocampus-dependent memory to impairment in the early preclinical stages of AD. Having identified the active species of Aβ that can play havoc with synaptic plasticity, it is hoped that new ways of targeting early AD can be developed.

scholarly journals A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons

2021 ◽  
pp. 1-20
Author(s):  
Yang Yu ◽  
Yang Gao ◽  
Bengt Winblad ◽  
Lars Tjernberg ◽  
Sophia Schedin Weiss
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Three Dimensional ◽  
Amyloid Β ◽  
Stimulated Emission ◽  
Amyloid Β Peptide ◽  
Primary Neurons ◽  
Amyloid Β Protein ◽  
Early Endosomes

Background: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ 42), which is a key player in Alzheimer’s disease. Objective: Our aim was to clarify the subcellular locations of the amyloidogenic AβPP processing in primary neurons, including the intracellular pools of the immediate substrate, AβPP C-terminal fragment (APP-CTF) and the product (Aβ 42). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. Methods: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional, three-channel imaging and image analyses. Results: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes in soma. Lack of colocalization of Aβ 42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ 42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ 42 were localized in different compartments. Conclusion: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.

Selective Secretase Targeting for Alzheimer’s Disease Therapy

2021 ◽  
pp. 1-17
Author(s):  
Alvaro Miranda ◽  
Enrique Montiel ◽  
Henning Ulrich ◽  
Cristian Paz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Neuroprotective Activity ◽  
Amyloid Β Protein ◽  
Secretase Activity ◽  
Membrane Bound ◽  
Aβ Production ◽  
Bace 1

Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

scholarly journals Case of early-onset Alzheimer’s disease with atypical manifestation

2021 ◽  
Vol 34 (1) ◽  
pp. e100283
Author(s):  
Lin Zhu ◽  
Limin Sun ◽  
Lin Sun ◽  
Shifu Xiao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Manifestation ◽  
Early Onset ◽  
Short Term Memory ◽  
Brain Mri ◽  
Memory Loss ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Fluent Aphasia

Short-term memory decline is the typical clinical manifestation of Alzheimer’s disease (AD). However, early-onset AD usually has atypical symptoms and may get misdiagnosed. In the present case study, we reported a patient who experienced symptoms of memory loss with progressive non-fluent aphasia accompanied by gradual social withdrawal. He did not meet the diagnostic criteria of AD based on the clinical manifestation and brain MRI. However, his cerebrospinal fluid examination showed a decreased level of beta-amyloid 42, and increased total tau and phosphorylated tau. Massive amyloid β-protein deposition by 11C-Pittsburgh positron emission tomography confirmed the diagnosis of frontal variant AD. This case indicated that early-onset AD may have progressive non-fluent aphasia as the core manifestation. The combination of individual and precision diagnosis would be beneficial for similar cases.

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