scholarly journals Both Amyloid-β Peptide and Tau Protein Are Affected by an Anti-Amyloid-β Antibody Fragment in Elderly 3xTg-AD Mice

2020 ◽  
Vol 21 (18) ◽  
pp. 6630 ◽  
Author(s):  
Alejandro R. Roda ◽  
Laia Montoliu-Gaya ◽  
Gabriel Serra-Mir ◽  
Sandra Villegas
Keyword(s):  
Psychological Symptoms ◽  
Early Stage ◽  
Amyloid Β ◽  
Antibody Fragment ◽  
Amyloid Β Peptide ◽  
Single Chain ◽  
Female Mice ◽  
Apolipoprotein J ◽  
Inflammatory State ◽  
Behavioral And Psychological Symptoms

Alzheimer’s disease (AD) is the most common dementia worldwide. According to the amyloid hypothesis, the early accumulation of the Aβ-peptide triggers tau phosphorylation, synaptic dysfunction, and eventually neuronal death leading to cognitive impairment, as well as behavioral and psychological symptoms of dementia. ScFv-h3D6 is a single-chain variable fragment that has already shown its ability to diminish the amyloid burden in 5-month-old 3xTg-AD mice. However, tau pathology is not evident at this early stage of the disease in this mouse model. In this study, the effects of scFv-h3D6 on Aβ and tau pathologies have been assessed in 22-month-old 3xTg-AD mice. Briefly, 3xTg-AD female mice were treated for 2 weeks with scFv-h3D6 and compared with 3xTg-AD and non-transgenic (NTg) mice treated with PBS. The treatment with scFv-h3D6 was unequivocally effective in reducing the area of Aβ staining. Furthermore, a tendency for a reduction in tau levels was also observed after treatment that points to the interplay between Aβ and tau pathologies. The pro-inflammatory state observed in the 3xTg-AD mice did not progress after scFv-h3D6 treatment. In addition, the treatment did not alter the levels of apolipoprotein E or apolipoprotein J. Thus, a 2-week treatment with scFv-h3D6 was able to reduce AD-like pathology in elderly 3xTg-AD female mice.

scholarly journals Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication

2017 ◽  
Vol 114 (25) ◽  
pp. 6444-6449 ◽  
Author(s):  
Anna Munke ◽  
Jonas Persson ◽  
Tanja Weiffert ◽  
Erwin De Genst ◽  
Georg Meisl ◽  
...  
Keyword(s):  
Phage Display ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Nucleation Process ◽  
Single Chain ◽  
Secondary Nucleation ◽  
Single Chain Antibody ◽  
Phage Display Libraries ◽  
Selection Of

The aggregation of the amyloid β peptide (Aβ) into amyloid fibrils is a defining characteristic of Alzheimer’s disease. Because of the complexity of this aggregation process, effective therapeutic inhibitors will need to target the specific microscopic steps that lead to the production of neurotoxic species. We introduce a strategy for generating fibril-specific antibodies that selectively suppress fibril-dependent secondary nucleation of the 42-residue form of Aβ (Aβ42). We target this step because it has been shown to produce the majority of neurotoxic species during aggregation of Aβ42. Starting from large phage display libraries of single-chain antibody fragments (scFvs), the three-stage approach that we describe includes (i) selection of scFvs with high affinity for Aβ42 fibrils after removal of scFvs that bind Aβ42 in its monomeric form; (ii) ranking, by surface plasmon resonance affinity measurements, of the resulting candidate scFvs that bind to the Aβ42 fibrils; and (iii) kinetic screening and analysis to find the scFvs that inhibit selectively the fibril-catalyzed secondary nucleation process in Aβ42 aggregation. By applying this approach, we have identified four scFvs that inhibit specifically the fibril-dependent secondary nucleation process. Our method also makes it possible to discard antibodies that inhibit elongation, an important factor because the suppression of elongation does not target directly the production of toxic oligomers and may even lead to its increase. On the basis of our results, we suggest that the method described here could form the basis for rationally designed immunotherapy strategies to combat Alzheimer’s and related neurodegenerative diseases.

scholarly journals β-site specific intrabodies to decrease and prevent generation of Alzheimer's Aβ peptide

2005 ◽  
Vol 168 (6) ◽  
pp. 863-868 ◽  
Author(s):  
Paolo Paganetti ◽  
Verena Calanca ◽  
Carmela Galli ◽  
Muriel Stefani ◽  
Maurizio Molinari
Keyword(s):  
Cleavage Site ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Single Chain ◽  
Cellular Events ◽  
Novel Approach ◽  
Er Retention ◽  
Intracellular Expression ◽  
The Brain

Endoproteolysis of the β-amyloid precursor protein (APP) by β- and γ-secretases generates the toxic amyloid β-peptide (Aβ), which accumulates in the brain of Alzheimer's disease (AD) patients. Here, we established a novel approach to regulate production of Aβ based on intracellular expression of single chain antibodies (intrabodies) raised to an epitope adjacent to the β-secretase cleavage site of human APP. The intrabodies rapidly associated, within the endoplasmic reticulum (ER), with newly synthesized APP. One intrabody remained associated during APP transport along the secretory line, shielded the β-secretase cleavage site and facilitated the alternative, innocuous cleavage operated by α-secretase. Another killer intrabody with an ER retention sequence triggered APP disposal from the ER. The first intrabody drastically inhibited and the second almost abolished generation of Aβ. Intrabodies association with specific substrates rather than with enzymes, may modulate intracellular processes linked to disease with highest specificity and may become instrumental to investigate molecular mechanisms of cellular events.

scholarly journals An anti-Aβ (amyloid β) single-chain variable fragment prevents amyloid fibril formation and cytotoxicity by withdrawing Aβ oligomers from the amyloid pathway

2011 ◽  
Vol 437 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Marta Marín-Argany ◽  
Geovanny Rivera-Hernández ◽  
Joaquim Martí ◽  
Sandra Villegas
Keyword(s):  
Conformational Changes ◽  
Amyloid Fibril ◽  
Recombinant Expression ◽  
Neuroblastoma Cell ◽  
Amyloid Β ◽  
Antibody Fragment ◽  
Temperature Perturbation ◽  
Single Chain ◽  
Aβ Oligomers ◽  
Aβ Amyloid

Aβ (amyloid β) immunotherapy has been revealed as a possible tool in Alzheimer's disease treatment. In contrast with complete antibodies, the administration of scFvs (single-chain variable fragments) produces neither meningoencephalitis nor cerebral haemorrhage. In the present study, the recombinant expression of scFv-h3D6, a derivative of an antibody specific for Aβ oligomers, is presented, as well as the subsequent proof of its capability to recover the toxicity induced by the Aβ1–42 peptide in the SH-SY5Y neuroblastoma cell line. To gain insight into the conformational changes underlying the prevention of Aβ toxicity by this antibody fragment, the conformational landscape of scFv-h3D6 upon temperature perturbation is also described. Heating the native state does not lead to any extent of unfolding, but rather directly to a β-rich intermediate state which initiates an aggregation pathway. This aggregation pathway is not an amyloid fibril pathway, as is that followed by the Aβ peptide, but rather a worm-like fibril pathway which, noticeably, turns out to be non-toxic. On the other hand, this pathway is thermodynamically and kinetically favoured when the scFv-h3D6 and Aβ1–42 oligomers form a complex in native conditions, explaining how the scFv-h3D6 withdraws Aβ1–42 oligomers from the amyloid pathway. To our knowledge, this is the first description of a conformational mechanism by which a scFv prevents Aβ-oligomer cytotoxicity.

scholarly journals Are there sensitive time periods for dementia caregivers? The occurrence of behavioral and psychological symptoms in the early stages of dementia

2013 ◽  
Vol 25 (9) ◽  
pp. 1453-1462 ◽  
Author(s):  
K. A. Ornstein ◽  
J. E. Gaugler ◽  
D. P. Devanand ◽  
N. Scarmeas ◽  
C. W. Zhu ◽  
...  
Keyword(s):  
Depressive Symptoms ◽  
Psychological Symptoms ◽  
Negative Impact ◽  
Early Stage ◽  
First Year ◽  
Dementia Patient ◽  
Dementia Diagnosis ◽  
Early Stages ◽  
Early Dementia ◽  
Behavioral And Psychological Symptoms

ABSTRACTBackground:The behavioral and psychological symptoms associated with dementia (BPSD) can be burdensome to informal/family caregivers, negatively affecting mental health and expediting the institutionalization of patients. Because the dementia patient–caregiver relationship extends over long periods of time, it is useful to examine how BPSD impact caregiver depressive symptoms at varied stages of illness. The goal of this study was to assess the association of BPSD that occur during early stage dementia with subsequent caregiver depressive symptoms.Methods:Patients were followed from the early stages of dementia every six months for up to 12 years or until death (n = 160). Caregiver symptoms were assessed on average 4.5 years following patient's early dementia behaviors. A generalized estimating equation (GEE) extension of the logistic regression model was used to determine the association between informal caregiver depressive symptoms and BPSD symptoms that occurred at the earliest stages dementia, including those persistent during the first year of dementia diagnosis.Results:BPSD were common in early dementia. None of the individual symptoms observed during the first year of early stage dementia significantly impacted subsequent caregiver depressive symptoms. Only patient agitation/aggression was associated with subsequent caregiver depressive symptoms (OR = 1.76; 95% CI = 1.04–2.97) after controlling for concurrent BPSD, although not in fully adjusted models.Conclusions:Persistent agitation/aggression early in dementia diagnosis may be associated with subsequent depressive symptoms in caregivers. Future longitudinal analyses of the dementia caregiving relationship should continue to examine the negative impact of persistent agitation/aggression in the diagnosis of early stage dementia on caregivers.

scholarly journals Effects of Amyloid Beta Peptide on Neurovascular Cells

2013 ◽  
Vol 1 (1) ◽  
Author(s):  
Sholpan Askarova ◽  
Andrey Tsoy ◽  
Tamara Shalakhmetova ◽  
James C-M Lee
Keyword(s):  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Treatment Strategies ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Amyloid Β Peptide ◽  
Inflammatory Reactions ◽  
Inflammatory Processes ◽  
The Brain

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder, which is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in specific regions of the brain, accompanied by impairment of the neurons, and progressive deterioration of cognition and memory of affected individuals. Although the cause and progression of AD are still not well understood, the amyloid hypothesis is dominant and widely accepted. According to this hypothesis, an increased deposition of amyloid-β peptide (Aβ) in the brain is the main cause of the AD’s onset and progression. There is increasing body of evidence that blood-brain barrier (BBB) dysfunction plays an important role in the development of AD, and may even precede neuron degeneration in AD brain. In the early stage of AD, microvasculature deficiencies, inflammatory reactions, surrounding the cerebral vasculature and endothelial dysfunctions are commonly observed. Continuous neurovascular degeneration and accumulation of Aβ on blood vessels resulting in cerebral amyloid angiopathy is associated with further progression of the disease and cognitive decline. However, little is known about molecular mechanisms that underlie Aβ induced damage of neurovascular cells. In this regards, this review is aimed to address how Aβ impacts the cerebral endothelium.  Understanding the cellular pathways triggered by Aβ leading to alterations in cerebral endothelial cells structure and functions would provide insights into the mechanism of BBB dysfunction and inflammatory processes in Alzheimer’s, and may offer new approaches for prevention and treatment strategies for AD. 

scholarly journals Involvement of hippocampal excitability in amyloid β-induced behavioral and psychological symptoms of dementia

2016 ◽  
Vol 41 (4) ◽  
pp. 449-457 ◽  
Author(s):  
Haruna Tamano ◽  
Kazuki Ide ◽  
Paul Anthony Adlard ◽  
Ashley Ian Bush ◽  
Atsushi Takeda
Keyword(s):  
Psychological Symptoms ◽  
Amyloid Β ◽  
Behavioral And Psychological Symptoms

scholarly journals Bacterial production and direct functional screening of expanded molecular libraries for discovering inhibitors of protein aggregation

2019 ◽  
Vol 5 (10) ◽  
pp. eaax5108 ◽  
Author(s):  
Dafni C. Delivoria ◽  
Sean Chia ◽  
Johnny Habchi ◽  
Michele Perni ◽  
Ilias Matis ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Early Stage ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Functional Screening ◽  
Parkinson’S Diseases ◽  
Aggregation Inhibitors ◽  
Molecular Libraries

Protein misfolding and aggregation are associated with a many human disorders, including Alzheimer’s and Parkinson’s diseases. Toward increasing the effectiveness of early-stage drug discovery for these conditions, we report a bacterial platform that enables the biosynthesis of molecular libraries with expanded diversities and their direct functional screening for discovering protein aggregation inhibitors. We illustrate this approach by performing, what is to our knowledge, the largest functional screen of small-size molecular entities described to date. We generated a combinatorial library of ~200 million drug-like, cyclic peptides and rapidly screened it for aggregation inhibitors against the amyloid-β peptide (Aβ42), linked to Alzheimer’s disease. Through this procedure, we identified more than 400 macrocyclic compounds that efficiently reduce Aβ42 aggregation and toxicity in vitro and in vivo. Finally, we applied a combination of deep sequencing and mutagenesis analyses to demonstrate how this system can rapidly determine structure-activity relationships and define consensus motifs required for bioactivity.

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