Tin oxide nanoparticles trigger the formation of amyloid β oligomers/protofibrils and underlying neurotoxicity as a marker of Alzheimer’s diseases

Alzheimer’s disease (AD) is known as one of the most common forms of dementia, and oligomerization of amyloid β (Aβ42) peptides can result in the onset of AD. Tin oxide nanoparticles (SnO2 NPs) showed several applications in biomedical fields can trigger unwanted interaction with proteins and inducing protein aggregation. Herein, we synthesized SnO2 NPs via the hydrothermal method and characterized by UV-visible, XRD, FTIR, TEM, and DLS techniques. Afterward, the formation of Aβ42 amyloid oligomers/protofibrils treated alone and with SnO2 NPs was explored by ThT and Nile red fluorescence and CD spectroscopic methods along with TEM imaging. The neurotoxicity of different spices of Aβ42 samples against PC-12 cells was then explored by MTT and caspase-3 activity assays.
The characterization of SnO2 NPs confirmed the successful synthesis of crystalline NPs (20-30 nm). Different biophysical and cellular analyses indicated that SnO2 NPs accelerated Aβ42 fibrillogenesis and promoted amyloid oligomers/protofibrils cytotoxicity. As compared to the Aβ42 samples grown alone, the ThT and ANS fluorescence intensity along with ellipticity results indicated the promotory effect of SnO2 NPs on the formation of oligomers/protofibrils. Also, the cellular results showed that the treated Aβ42 samples with SnO2 NPs further reduced cell viability through activation of caspase-3. In conclusion, SnO2 NPs greatly accelerate the fibrillation of Aβ42 peptides and lead to the formation of more toxic species. The present data may offer further warrants into nano-based systems for biomedical applications in the central nervous system.

New Alzheimer models for drug screening based on improved human amyloid beta (1-42) oligomer preparations

The etiology of Alzheimer’s disease (AD) is poorly understood. A growing body of literature suggests that amyloid beta oligomers (AβO) as the root cause of this disease. Here, we describe new translational in vitro and in vivo models of AD, induced by minute amount of in-house preparation of human AβO.
AβO were reproducibly prepared from human Aβ 1-42 monomers. Rodent primary neurons were used to assess the neurotoxic activities of AβO in vitro and elderly wild-type mice administered by a single intracerebral injection AβO in vivo.
The oligomeric preparations were characterized by SDS-page, electron microscopy and dot-plot tests. In vitro, AβO induced a dose-dependent neurodegeneration on rodent primary neurons based on various read-outs. Interestingly, neurotoxicity was greater with AβO than fibrillar Aβ, while Aβ monomers did not induce any neuronal damage. AβO-induced neurotoxicity was significantly attenuated by brain-derived neurotrophic factor (BDNF). In vivo, a single intracerebral microinjection of AβO in 18-month-old wild-type mice, led to a significant memory impairment, synaptic loss in hippocampus and increased secretion of brain proinflammatory cytokines 15 days post administration. Moreover, the memory deficits were significantly reversed with Donepezil used as reference drug.
In conclusion, we characterized new tools for drug screening based on the soluble AβO hypothesis of AD. In vivo, this new non-inherited Alzheimer model can be used both to evaluate disease modifying and symptomatic drugs. Finally, these models are also valuable tools to understand the mechanisms underlying AD.

Amyloid-β oligomers in the nucleus accumbens decrease motivation via insertion of calcium-permeable AMPA receptors

It is essential to identify the neuronal mechanisms of Alzheimer’s Disease (AD)-associated neuropsychiatric symptoms, e.g., apathy, before improving the life quality of AD patients. Here, we focused on the nucleus accumbens (NAc), a critical brain region processing motivation, also known to display AD-associated pathological changes in human cases. We found that the synaptic calcium permeable (CP)-AMPA receptors (AMPARs), which are normally absent in the NAc, can be revealed by acute exposure to Aβ oligomers (AβOs), and play a critical role in the emergence of synaptic loss and motivation deficits. Blockade of NAc CP-AMPARs can effectively prevent AβO-induced downsizing and pruning of spines and silencing of excitatory synaptic transmission. We conclude that AβO-triggered synaptic insertion of CP-AMPARs is a key mechanism mediating synaptic degeneration in AD, and preserving synaptic integrity may prevent or delay the onset of AD-associated psychiatric symptoms.

Hybridization chain reaction triggered poly adenine to absorb silver nanoparticles for label-free electrochemical detection of Alzheimer’s disease biomarkers amyloid β-peptide oligomers

Amyloid β-peptide oligomer (AβO) has received extensive attention from researchers because of its clinical therapeutic intervention targets and the value of reliable biological macromolecules markers for early diagnosis of Alzheimer’s disease. We have developed a novel label-free electrochemical detection sensor for AβO based on hybridization chain reaction (HCR)-triggered poly adenine to absorb silver nanoparticles (AgNPs). In this method, we first use the “capture probe” to immobilize the aptamer 1 on the surface of the gold electrode (GE) via poly adenine-Au. Next, aptamer 2 and AβO were deposited on the electrode surface.
The HCR process was initiated by the aptamer 2 fragment as a primer, producing a large number of long DNA sequences, which contained many adenines. Thereafter, the HCR product with long-repeated adenines could absorb many AgNPs on the surface of the electrode, which were used for subsequent electrochemical stripping of the AgNPs. The concentration range of the electrochemical signal of AβO was 1 pM-10 nM, and the detection limit was 430 fM, which indicated that that the detection system has high selectivity for the target protein.

Protection against Amyloid-β Oligomer Neurotoxicity by Small Molecules with Antioxidative Properties: Potential for the Prevention of Alzheimer’s Disease Dementia

Soluble oligomeric assemblies of amyloid β-protein (Aβ), called Aβ oligomers (AβOs), have been recognized as primary pathogenetic factors in the molecular pathology of Alzheimer’s disease (AD). AβOs exert neurotoxicity and synaptotoxicity and play a critical role in the pathological progression of AD by aggravating oxidative and synaptic disturbances and tau abnormalities. As such, they are important therapeutic targets. From a therapeutic standpoint, it is not only important to clear AβOs or prevent their formation, it is also beneficial to reduce their neurotoxicity.

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In this regard, recent studies have reported that small molecules, most with antioxidative properties, show promise as therapeutic agents for reducing the neurotoxicity of AβOs. In this mini-review, we briefly review the significance of AβOs and oxidative stress in AD and summarize studies on small molecules with AβO-neurotoxicity-reducing effects. We also discuss mechanisms underlying the effects of these compounds against AβO neurotoxicity as well as their potential as drug candidates for the prevention and treatment of AD.