Prion protein stabilizes amyloid-β (Aβ) oligomers and enhances Aβ neurotoxicity in aDrosophilamodel of Alzheimer's disease

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

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Cu-Based Turn-on Fluorescent Sensors for Cu-rich Amyloid β Aggregates

10.26434/chemrxiv.14191865.v1 ◽

2021 ◽

Author(s):

Yiran Huang ◽

Liang Sun ◽

Liviu M. Mirica

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fluorescence Imaging ◽

Protein Misfolding ◽

Picolinic Acid ◽

Amyloid Β ◽

Fluorescent Sensors ◽

Aβ Oligomers ◽

Turn On ◽

Aβ Aggregation

<div>Protein misfolding and metal dishomeostasis are two key</div><div>pathological factors of Alzheimer’s disease. Previous studies have showed that Cu‐mediated Aβ aggregation pathways lead to formation of neurotoxic Aβ oligomers. Herein, we reported a series of picolinic acid‐based Cu‐activatable sensors, which can be used for the fluorescence imaging of Cu‐rich Aβ aggregates.</div>

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Prions and Neurodegenerative Diseases: A Focus on Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-215171 ◽

2021 ◽

pp. 1-16

Author(s):

Alessio Crestini ◽

Francesca Santilli ◽

Stefano Martellucci ◽

Elena Carbone ◽

Maurizio Sorice ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Amyloid Β ◽

Specific Protein ◽

Cellular Prion Protein ◽

Aβ Oligomers ◽

The Central Nervous System ◽

Induced Signal

Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer’s disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.

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The inhibition of cellular toxicity of amyloid-β by dissociated transthyretin

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013440 ◽

2020 ◽

Vol 295 (41) ◽

pp. 14015-14024 ◽

Cited By ~ 1

Author(s):

Qin Cao ◽

Daniel H. Anderson ◽

Wilson Y. Liang ◽

Joshua Chou ◽

Lorena Saelices

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protective Effect ◽

Amyloid Β ◽

Inhibitory Effect ◽

Aβ Oligomers ◽

Cellular Toxicity ◽

Computational Docking

The protective effect of transthyretin (TTR) on cellular toxicity of β-amyloid (Aβ) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, the pathogenic aggregation of which causes systemic amyloidosis. However, studies have documented a protective effect of TTR against cellular toxicity of pathogenic Aβ, a protein associated with Alzheimer's disease. TTR binds Aβ, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we investigate whether the amyloidogenic ability of TTR and its antiamyloid inhibitory effect are associated. Using protein aggregation and cytotoxicity assays, we found that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers. These findings suggest that the Aβ-binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aβ aggregation and toxicity, mimicking TTR cellular protection. EM, immune detection analysis, and assessment of aggregation and cytotoxicity revealed that the TTR segment inhibits Aβ oligomer formation and also promotes the formation of nontoxic, nonamyloid amorphous aggregates, which are more sensitive to protease digestion. Finally, this segment also inhibits seeding of Aβ catalyzed by Aβ fibrils extracted from the brain of an Alzheimer's patient. Together, these findings suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer's disease.

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Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21165858 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5858 ◽

Cited By ~ 3

Author(s):

Md. Sahab Uddin ◽

Md. Tanvir Kabir ◽

Md. Sohanur Rahman ◽

Tapan Behl ◽

Philippe Jeandet ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Clinical Symptoms ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Amyloid Β ◽

Aβ Oligomers ◽

Aβ Aggregation ◽

Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

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Synaptic memory mechanisms: Alzheimer's disease amyloid β-peptide-induced dysfunction

Biochemical Society Transactions ◽

10.1042/bst0351219 ◽

2007 ◽

Vol 35 (5) ◽

pp. 1219-1223 ◽

Cited By ~ 90

Author(s):

M.J. Rowan ◽

I. Klyubin ◽

Q. Wang ◽

N.W. Hu ◽

R. Anwyl

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Nitrosative Stress ◽

Amyloid Β ◽

Long Term Potentiation ◽

Amyloid Β Peptide ◽

Aβ Oligomers ◽

Aβ Amyloid

There is growing evidence that mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Aβ (amyloid β-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Aβ oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for Aβ, the αv integrin extracellular cell matrix-binding protein and the cytokine TNFα (tumour necrosis factor α) type-1 death receptor mediate Aβ oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNFα or genetic knockout of TNF-R1s (type-1 TNFα receptors) prevented Aβ-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to αv-containing integrins abrogated LTP block by Aβ. Protection against the synaptic plasticity-disruptive effects of soluble Aβ was also achieved using systemically administered small molecules targeting these mechanisms in vivo. Taken together, this research lends support to therapeutic trials of drugs antagonizing synaptic plasticity-disrupting actions of Aβ oligomers in preclinical AD.

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Soluble Prion Peptide 107–120 Protects Neuroblastoma SH-SY5Y Cells against Oligomers Associated with Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21197273 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7273

Author(s):

Elham Rezvani Boroujeni ◽

Seyed Masoud Hosseini ◽

Giulia Fani ◽

Cristina Cecchi ◽

Fabrizio Chiti

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Critical Role ◽

Amyloid Β ◽

Cellular Prion Protein ◽

Ros Generation ◽

Aβ Oligomers ◽

Self Recognition ◽

High Affinity Receptor

Alzheimer’s disease (AD) is the most prevalent form of dementia and soluble amyloid β (Aβ) oligomers are thought to play a critical role in AD pathogenesis. Cellular prion protein (PrPC) is a high-affinity receptor for Aβ oligomers and mediates some of their toxic effects. The N-terminal region of PrPC can interact with Aβ, particularly the region encompassing residues 95–110. In this study, we identified a soluble and unstructured prion-derived peptide (PrP107–120) that is external to this region of the sequence and was found to successfully reduce the mitochondrial impairment, intracellular ROS generation and cytosolic Ca2+ uptake induced by oligomeric Aβ42 ADDLs in neuroblastoma SH-SY5Y cells. PrP107–120 was also found to rescue SH-SY5Y cells from Aβ42 ADDL internalization. The peptide did not change the structure and aggregation pathway of Aβ42 ADDLs, did not show co-localization with Aβ42 ADDLs in the cells and showed a partial colocalization with the endogenous cellular PrPC. As a sequence region that is not involved in Aβ binding but in PrP self-recognition, the peptide was suggested to protect against the toxicity of Aβ42 oligomers by interfering with cellular PrPC and/or activating a signaling that protected the cells. These results strongly suggest that PrP107–120 has therapeutic potential for AD.

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Amyloid toxicity in Alzheimer’s disease

Reviews in the Neurosciences ◽

10.1515/revneuro-2017-0063 ◽

2018 ◽

Vol 29 (6) ◽

pp. 613-627 ◽

Cited By ~ 80

Author(s):

Allison B. Reiss ◽

Hirra A. Arain ◽

Mark M. Stecker ◽

Nicolle M. Siegart ◽

Lora J. Kasselman

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pore Formation ◽

Amyloid Β ◽

Precursor Protein ◽

Calcium Balance ◽

Aβ Oligomers ◽

Synaptic Loss ◽

Amyloid Toxicity ◽

Aβ Production

Abstract A major feature of Alzheimer’s disease (AD) pathology is the plaque composed of aggregated amyloid-β (Aβ) peptide. Although these plaques may have harmful properties, there is much evidence to implicate soluble oligomeric Aβ as the primary noxious form. Aβ oligomers can be generated both extracellularly and intracellularly. Aβ is toxic to neurons in a myriad of ways. It can cause pore formation resulting in the leakage of ions, disruption of cellular calcium balance, and loss of membrane potential. It can promote apoptosis, cause synaptic loss, and disrupt the cytoskeleton. Current treatments for AD are limited and palliative. Much research and effort is being devoted to reducing Aβ production as an approach to slowing or preventing the development of AD. Aβ formation results from the amyloidogenic cleavage of human amyloid precursor protein (APP). Reconfiguring this process to disfavor amyloid generation might be possible through the reduction of APP or inhibition of enzymes that convert the precursor protein to amyloid.

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CNI-1493 inhibits Aβ production, plaque formation, and cognitive deterioration in an animal model of Alzheimer's disease

Journal of Experimental Medicine ◽

10.1084/jem.20060467 ◽

2008 ◽

Vol 205 (7) ◽

pp. 1593-1599 ◽

Cited By ~ 14

Author(s):

Michael Bacher ◽

Richard Dodel ◽

Bayan Aljabari ◽

Kathy Keyvani ◽

Philippe Marambaud ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Performance ◽

Amyloid Β ◽

Amyloid Plaque ◽

Amyloid Β Protein ◽

Aβ Oligomers ◽

App Processing ◽

Model Of Alzheimer’S Disease

Alzheimer's disease (AD) is characterized by neuronal atrophy caused by soluble amyloid β protein (Aβ) peptide “oligomers” and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. We show that CNI-1493, a tetravalent guanylhydrazone with established antiinflammatory properties, interferes with Aβ assembly and protects neuronal cells from the toxic effect of soluble Aβ oligomers. Administration of CNI-1493 to TgCRND8 mice overexpressing human amyloid precursor protein (APP) for a treatment period of 8 wk significantly reduced Aβ deposition. CNI-1493 treatment resulted in 70% reduction of amyloid plaque area in the cortex and 87% reduction in the hippocampus of these animals. Administration of CNI-1493 significantly improved memory performance in a cognition task compared with vehicle-treated mice. In vitro analysis of CNI-1493 on APP processing in an APP-overexpressing cell line revealed a significant dose-dependent decrease of total Aβ accumulation. This study indicates that the antiinflammatory agent CNI-1493 can ameliorate the pathophysiology and cognitive defects in a murine model of AD.

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