Accumulation Of Β-amyloid Protein Research Articles

The Absence of Myelin Basic Protein Reduces Non-Amyloidogenic Processing of Amyloid Precursor Protein.

The accumulation of amyloid β-protein (Aβ) in the brain is a pathological feature of Alzheimer's disease (AD). Aβ peptides originate from amyloid precursor protein (APP). APP can be proteolytically cleaved through amyloidogenic or non-amyloidogenic pathways. The molecular effects on APP metabolism/processing may be influenced by myelin and the breakdown of myelin basic protein (MBP) in AD patients and mouse models of AD pathology. We directly tested whether MBP can alter influence APP processing in MBP-/- mice, known as Shiverer (shi/shi) mice, in which no functional MBP is produced due to gene breakage from the middle of MBP exon ll. A significant reduction of the cerebral sAPPα level in Shiverer (shi/shi) mice was found, although the levels of both total APP and sAPPβ remain unchanged. The reduction of sAPPα was considered to be due to the changes in the expression levels of a disintegrin and metalloproteinase-9 (ADAM9) catalysis and non-amyloid genic processing of APP in the absence of MBP because it binds to ADAM9. MBP -/- mice exhibited increased Aβ oligomer production. These findings suggest that in the absence of MBP, there is a marked reduction of nonamyloidogenic APP processing to sAPPα, and targeting myelin of oligodendrocytes may be a novel therapy for the prevention and treatment of AD.

Intranasal Insulin Administration to Prevent Delayed Neurocognitive Recovery and Postoperative Neurocognitive Disorder: A Narrative Review.

Delayed neurocognitive recovery and postoperative neurocognitive disorders are major complications of surgery, hospitalization, and anesthesia that are receiving increasing attention. Their incidence is reported to be 10–80% after cardiac surgery and 10–26% after non-cardiac surgery. Some of the risk factors include advanced age, level of education, history of diabetes mellitus, malnutrition, perioperative hyperglycemia, depth of anesthesia, blood pressure fluctuation during surgery, chronic respiratory diseases, etc. Scientific evidence suggests a causal association between anesthesia and delayed neurocognitive recovery or postoperative neurocognitive disorders, and various pathophysiological mechanisms have been proposed: mitochondrial dysfunction, neuroinflammation, increase in tau protein phosphorylation, accumulation of amyloid-β protein, etc. Insulin receptors in the central nervous system have a non-metabolic role and act through a neuromodulator-like action, while an interaction between anesthetics and central nervous system insulin receptors might contribute to anesthesia-induced delayed neurocognitive recovery or postoperative neurocognitive disorders. Acute or chronic intranasal insulin administration, which has no influence on the blood glucose concentration, appears to improve working memory, verbal fluency, attention, recognition of objects, etc., in animal models, cognitively healthy humans, and memory-impaired patients by restoring the insulin receptor signaling pathway, attenuating anesthesia-induced tau protein hyperphosphorylation, etc. The aim of this review is to report preclinical and clinical evidence of the implication of intranasal insulin for preventing changes in the brain molecular pattern and/or neurobehavioral impairment, which influence anesthesia-induced delayed neurocognitive recovery or postoperative neurocognitive disorders.

Effects of Ions and Small Compounds on the Structure of Aβ42 Monomers

Aggregation of amyloid-β (Aβ) proteins in the brain is a hallmark of Alzheimer's disease. This phenomenon can be promoted or inhibited by adding small molecules to the solution where Aβ is embedded. These molecules affect the ensemble of conformations sampled by Aβ monomers even before aggregation starts. Here, we perform extensive all-atom replica exchange molecular dynamics (REMD) simulations to provide a comparative study of the ensemble of conformations sampled by Aβ42 monomers in solutions that promote (i.e., aqueous solution containing NaCl) and inhibit (i.e., aqueous solutions containing scyllo-inositol or 4-aminophenol) aggregation. Simulations performed in pure water are used as our reference. We find that secondary-structure content is only affected in an antagonistic manner by promoters and inhibitors at the C-terminus and the central hydrophilic core. Moreover, the end of the C-terminus binds more favorably to the central hydrophobic core region of Aβ42 in NaCl adopting a type of strand-loop-strand structure that is disfavored by inhibitors. Nonpolar residues that form the dry core of larger aggregates of Aβ42 (e.g., PDB ID 2BEG) are found at close proximity in these strand-loop-strand structures, suggesting that their formation could play an important role in initiating nucleation. In the presence of inhibitors, the C-terminus binds the central hydrophilic core with a higher probability than in our reference simulation. This sensitivity of the C-terminus, which is affected in an antagonistic manner by inhibitors and promoters, provides evidence for its critical role in accounting for aggregation.

Novel sampangine derivatives as potent inhibitors of Cu2+-mediated amyloid-β protein aggregation, oxidative stress and inflammation

A series of 11-substituted sampangine derivatives have been designed, synthesized, and tested for their ability to inhibit cholinesterase. Their chelating ability and selectivity for Cu2+ over other biologically relevant metal ions were demonstrated by isothermal titration calorimetry. Their blood-brain barrier permeability was also tested by parallel artificial membrane permeation assay. Among the synthesized derivatives, compound 11 with the strong anti-acetylcholinesterase activity, high blood-brain barrier penetration ability and high binding affinity to Cu2+ was selected for further research. Western blotting analysis, transmission electron microscopy, DCFH-DA assay and paralysis experiment indicated that compound 11 suppressed the formation of Cu2+-Aβ complexes, alleviated the Cu2+ induced neurotoxicity and inhibited the production of ROS catalyzed by Cu2+ in Aβ42 transgenic C. elegans. Moreover, compound 11 also inhibited the expressions of proinflammatory cytokines, such as NO, TNF-α, IL-6 and IL-1β, induced by Cu2+ + Aβ1–42 in BV2 microglial cells. In general, this work provided new insights into the design and development of potent metal-chelating agents for AD treatment.

Biological analysis of woodpecker’s brain after impact experiments

Woodpeckers can withstand a fierce impact during pecking. Previous studies have focused on the biomechanical analysis of the pecking process, the properties of the beak and hyoid bone of woodpecker; however, the biological characteristics of the woodpecker brain are also important in resisting impact injuries. We employed impact experiments and biological analysis in normal and injured brains to reveal the impact-resistant biological characteristics of woodpecker brains, as well as the impact energy’s biological effects on the woodpecker brain. The hoopoe, which has a similar size but only a slight pecking behavior, was selected as the control group to compare brain morphology and neuronal cells differences in normal brains between woodpecker and hoopoe by sectioning and staining. A loading device was designed to conduct a quantifiable impact energy to the woodpeckers’ head. Four groups of woodpeckers were impacted with the same energy on the forehead, beak, tempus and occiput, respectively. Biological changes in the injured brains were evaluated by Nissl staining and enzyme-linked immunosorbent assay. The results showed that: (1) woodpeckers had a larger cerebellum and a higher density of Nissl bodies than hoopoe; (2) Nissl apoptosis appeared in the brain samples after the forehead and the occiput impact experiments, but no obvious Nissl body apoptosis was observed after impact on the tempus and the beak; (3) β-amyloid protein accumulated in the normal status woodpecker brain. This study reveals that: woodpecker brain morphology is well-adapted to impact, woodpecker heads display location-dependent protective performance, with beak and tempus regions having a better protective performance than the forehead and occiput, Nissl apoptosis appears in injured woodpecker brains, and that the accumulation of β-amyloid protein does not show a direct relationship with the injury state of woodpecker’s brain tissue in our study.

Molecular Insight into Cu2+-Induced Conformational Transitions of Amyloid β-Protein from Fast Kinetic Analysis and Molecular Dynamics Simulations.

Cu2+-mediated amyloid β-protein (Aβ) aggregation is implicated in the pathogenesis of Alzheimer's disease, so it is of significance to understand Cu2+-mediated conformational transitions of Aβ. Herein, four Aβ mutants were created by using the environment-sensitive cyanophenylalanine to respectively substitute F4, Y10, F19, and F20 residues of Aβ40. By using stopped-flow fluorescence spectroscopy and molecular dynamics (MD) simulations, the early stage conformational transitions of the mutants mediated by Cu2+ binding were investigated. The fast kinetics unveils that Cu2+ has more significant influence on the conformational changes of N-terminal (F4 and Y10) than on the central hydrophobic core (CHC, F19, and F20) under different pH conditions (pH 6.6-8.0), especially Y10. Interestingly, lag periods of the conformational transitions are observed for the F19 and F20 mutants at pH 8.0, indicating the slow response of the two mutation sites on the conformational transitions. More importantly, significantly longer lag periods for F20 than for F19 indicate the conduction of the transition from F19 to F20. The conduction time (difference in lag period) decreases from 4.5 s at Cu2+ = 0 to undetectable (<1 ms) at Cu2+ = 10 μM. The significant difference in the response time of F19 and F20 and the fast local conformational changes of Y10 imply that the conformational transitions of Aβ start around Y10. MD simulations support the observation of hydrophobicity increase at N-terminal during the conformational transitions of Aβ-Cu2+. It also reveals that Y10 is immediately approached by Cu2+, supporting the speculation that the starting point of conformational transitions of Aβ is near Y10. The work has provided molecular insight into the early stage conformational transitions of Aβ40 mediated by Cu2+.

Molecular mechanisms of resveratrol and EGCG in the inhibition of Aβ42 aggregation and disruption of Aβ42 protofibril: similarities and differences.

The aggregation of amyloid-β protein (Aβ) into fibrillary deposits is implicated in Alzheimer's disease (AD), and inhibiting Aβ aggregation and clearing Aβ fibrils are considered as promising strategies to treat AD. It has been reported that resveratrol (RSV) and epigallocatechin-3-gallate (EGCG), two of the most extensively studied natural polyphenols, are able to inhibit Aβ fibrillization and remodel the preformed fibrillary aggregates into amorphous, non-toxic species. However, the mechanisms by which RSV inhibits Aβ42 aggregation and disrupts Aβ42 protofibril, as well as the inhibitory/disruptive mechanistic similarities and differences between RSV and EGCG, remain mostly elusive. Herein, we performed extensive all-atom molecular dynamics (MD) simulations on Aβ42 dimers (the early aggregation state of Aβ42) and protofibrils (the intermediate of Aβ42 fibril formation and elongation) in the absence/presence of RSV or EGCG molecules. Our simulations show that both RSV and EGCG can bind with Aβ42 monomers and inhibit the dimerization of Aβ42. The binding of RSV with Aβ42 peptide is mostly viaπ-π stacking interactions, while the binding of EGCG with Aβ42 is mainly through hydrophobic, π-π stacking, and hydrogen-bonding interactions. Moreover, both RSV and EGCG disrupt the β-sheet structure and K28-A42 salt bridges, leading to a disruption of Aβ42 protofibril structure. RSV mainly binds with residues whose side-chains point inwards from the surface of the protofibril, while EGCG mostly binds with residues whose side-chains point outwards from the surface of the protofibril. Furthermore, RSV interacts with Aβ42 protofibrils mostly viaπ-π stacking interactions, while EGCG interacts with Aβ42 protofibrils mainly via hydrogen-bonding and hydrophobic interactions. For comparison, we also explore the effects of RSV/EGCG molecules on the aggregation inhibition and protofibril disruption of the Iowa mutant (D23N) Aβ. Our findings may pave the way for the design of more effective drug candidates as well as the utilization of cocktail therapy using RSV and EGCG for the treatment of AD.

The effects of antimony on Alzheimer's disease-like pathological changes in mice brain

We have previously identified antimony (Sb) as a newly nerve poison which leads to neuronal apoptosis. However, the relationship between Sb exposure and Alzheimer's disease (AD) process lacks direct evidence. HE staining and Nissl staining showed significant nerve damage after Sb exposure. Therefore, we further evaluated Sb-associated AD risk by detecting accumulation of β-amyloid protein (Aβ) and neurofibrillary tangles (NFTs) in the brains of mice exposed to Sb for 4 and 8 weeks, and even 1 year. The results showed that dose of 20 mg/kg induced Aβ accumulation, but not tau hyperphosphorylation after exposure for 4 week. Eight weeks later, both 10 and 20 mg/kg dramatically triggered Aβ accumulation and increased tau phosphorylation at ser199. At the same time, 20 mg/kg could also increase tau phosphorylation at ser396 and number of NFTs. One years later, we found all of AD hallmarks detected in present study showed positive results in the brains of mice exposed to Sb at 10 and 20 mg/kg. In summary, our data provided direct evidence of Sb-associated AD risk, drawing more attention to Sb-triggered neurotoxicity.

Thermal cycling protects SH-SY5Y cells against hydrogen peroxide and β-amyloid-induced cell injury through stress response mechanisms involving Akt pathway.

Neurodegenerative diseases (NDDs) are becoming a major threat to public health, according to the World Health Organization (WHO). The most common form of NDDs is Alzheimer’s disease (AD), boasting 60–70% share. Although some debates still exist, excessive aggregation of β-amyloid protein (Aβ) and neurofibrillary tangles has been deemed one of the major causes for the pathogenesis of AD. A growing number of evidences from studies, however, have suggested that reactive oxygen species (ROS) also play a key role in the onset and progression of AD. Although scientists have had some understanding of the pathogenesis of AD, the disease still cannot be cured, with existing treatment only capable of providing a temporary relief at best, partly due to the obstacle of blood-brain barrier (BBB). The study was aimed to ascertain the neuroprotective effect of thermal cycle hyperthermia (TC-HT) against hydrogen peroxide (H2O2) and Aβ-induced cytotoxicity in SH-SY5Y cells. Treating cells with this physical stimulation beforehand significantly improved the cell viability and decreased the ROS content. The underlying mechanisms may be due to the activation of Akt pathway and the downstream antioxidant and prosurvival proteins. The findings manifest significant potential of TC-HT in neuroprotection, via inhibition of oxidative stress and cell apoptosis. It is believed that coupled with the use of drugs or natural compounds, this methodology can be even more effective in treating NDDs.

Impact of Mutations on the Conformational Transition from α-Helix to β-Sheet Structures in Arctic-Type Aβ40: Insights from Molecular Dynamics Simulations

The amyloid-β (Aβ) protein aggregation into toxic oligomers and fibrils has been recognized as a key player in the pathogenesis of Alzheimer’s disease. Recent experiments reported that a double alanine mutation (L17A/F19A) in the central hydrophobic core (CHC) region of [G22]Aβ40 (familial Arctic mutation) diminished the self-assembly propensity of [G22]Aβ40. However, the molecular mechanism behind the decreased aggregation tendency of [A17/A19/G22]Aβ40 is not well understood. Herein, we carried out molecular dynamics simulations to elucidate the structure and dynamics of [G22]Aβ40 and [A17/A19/G22]Aβ40. The results for the secondary structure analysis reveal a significantly increased amount of the helical content in the CHC and C-terminal region of [A17/A19/G22]Aβ40 as compared to [G22]Aβ40. The bending free-energy analysis of D23–K28 salt bridge suggests that the double alanine mutation in the CHC region of [G22]Aβ40 has the potential to reduce the fibril formation rate by 0.57 times of [G22]Aβ40. Unlike [G22]Aβ40, [A17/A19/G22]Aβ40 largely sampled helical conformation, as determined by the minimum energy conformations extracted from the free-energy landscape. The present study provided atomic level details into the experimentally observed diminished aggregation tendency of [A17/A19/G22]Aβ40 as compared to [G22]Aβ40.

Dual Effect of the Acidic Polysaccharose Ulvan on the Inhibition of Amyloid-β Protein Fibrillation and Disintegration of Mature Fibrils.

The abnormal folding and aggregation of amyloid-β protein (Aβ) is the main reason for the occurrence and development of Alzheimer's disease (AD). The discovery of novel inhibitors against Aβ aggregation is still the current research focus. Herein, we report the inhibitory effect of ulvan, an acidic polysaccharide from green algae of the genus Ulva, against Aβ fibrillation using thioflavin T (ThT) fluorescence and atomic force microscopy (AFM) assays. It is shown that ulvan effectively inhibits Aβ fibrillogenesis in a concentration-dependent manner and actively inhibits the formation of A11-reactive Aβ oligomers, the most toxic Aβ species. The circular dichroism spectrum reveals that ulvan blocks the conformational transition of Aβ40 from the initial random coil to a β-sheet structure, but it only delays the conformational transition of Aβ42. It is also found that ulvan greatly reduces Aβ-induced cytotoxicity by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, ulvan effectively downregulates intracellular reactive oxygen species production and protects PC12 cells from the damage caused by Aβ fibrillation. Moreover, ulvan disaggregates preformed mature fibrils into off-pathway oligomers and greatly decreases their associated cytotoxicity, as revealed using ThT fluorescence, AFM, MTT, and dot-blotting assays. The above results not only fully describe the inhibitory effect of ulvan on Aβ fibrillation and its related cytotoxicity but also provide novel ideas for the development of functional food ingredients from seaweed to treat AD.

Design and synthesis of β-strand-fixed peptides inhibiting aggregation of amyloid β-protein

Aggregation of 42-residue amyloid β-protein (Aβ42) can be prevented by β-sheet breaker peptides (BSBps) homologous to LVFFA residues, which are included in a β-sheet region of Aβ42 aggregates. To enhance the affinity of BSBps to the Aβ42 aggregates, we designed and synthesized β-strand-fixed peptides (BSFps) whose side chains were cross-linked by ring closing metathesis. Conformation analysis verified that the designed peptides could be fixed in β-strand conformation. Among the synthesized pentapeptides, 1 and 12, whose side chains of 2nd and 4th residues were cross-linked, significantly inhibited the aggregation of Aβ42. This suggested that β-strand-fixation of BSBps could enhance their inhibitory activity against the Aβ42 aggregation. However, pentapeptides 1 and 12 had little effect on morphology of Aβ42 aggregates (fibrils) and neurotoxicity of Aβ42 against SH-SY5Y cells.

Hydroxycinnamic Acid from Corncob and Its Structural Analogues Inhibit Aβ40 Fibrillation and Attenuate Aβ40-Induced Cytotoxicity.

The aggregation of amyloid-β protein (Aβ) is deemed a vital pathological feature of Alzheimer's disease (AD). Hence, inhibiting Aβ aggregation is noticed as a major tactic for the prevention and therapy of AD. Hydroxycinnamic acid, as a natural phenolic compound, is widely present in plant foods and has several biological activities including anti-inflammation, antioxidation, and neuroprotective effects. Here, it was found that hydroxycinnamic acid and its structural analogues (3-hydroxycinnamic acid, 2-hydroxycinnamic acid, cinnamic acid, 3,4-dihydroxycinnamic acid, 2,4-dihydroxycinnamic acid, and 3,4,5-trihydroxycinnamic acid) could inhibit Aβ40 fibrillogenesis and reduce Aβ40-induced cytotoxicity in a dose-dependent manner. Among these small molecules investigated, 3,4,5-trihydroxycinnamic acid is considered to be the most effective inhibitor, which reduces the ThT fluorescence intensity to 30.79% and increases cell viability from 49.47 to 84.78% at 200 μM. Also, the results with Caenorhabditis elegans verified that these small molecules can ameliorate AD-like symptoms of worm paralysis. Moreover, molecular docking studies showed that these small molecules interact with the Aβ40 mainly via hydrogen bonding. These results suggest that hydroxycinnamic acid and its structural analogues could inhibit Aβ40 fibrillogenesis and the inhibition activity is enhanced with the increase of phenolic hydroxyl groups of inhibitors. These small molecules have huge potential to be developed into novel aggregation inhibitors in neurodegenerative disorders.

Heptameric Peptide Interferes with Amyloid-β Aggregation by Structural Reorganization of the Toxic Oligomers.

Pathogenesis of Alzheimer’s disease (AD), the most common type of dementia, involves misfolding and aggregation of the extracellular amyloid-β (Aβ) protein where the intermediate oligomers, formed during the aggregation progression cascade, are considered the prime toxic species. Here, we identify an active peptide fragment from a medicinal plant-derived (Aristolochia indica) fibrinolytic enzyme having anti-amyloidogenic effects against Aβ fibrillation and toxicity. Liquid chromatography with tandem mass spectrometry (LC-MS/MS), followed by computational analysis of the peptide pool generated by proteolytic digestion of the enzyme, identifies two peptide sequences with predictive high-propensity binding to Aβ42. Microscopic visualizations in conjunction with biochemical and biophysical assessments suggest that the synthetic version of one of the peptides (termed here Pactive, GFLLHQK) arrests Aβ molecules in off-pathway oligomers that can no longer participate in the cytotoxic fibrillation pathway. In contrast, the other peptide (termed P1) aggravates the fibrillation process. Further investigations confirm the strong binding affinity of Pactive with both Aβ42 monomers and toxic oligomers by biolayer interferometric assays. We have also shown that, mechanistically, Pactive binding induces conformational alterations in the Aβ molecule along with modification of Aβ hydrophobicity, one of the key players in aggregation. Importantly, the biostability of Pactive in human blood serum and its nontoxic nature make it a promising therapeutic candidate against Alzheimer’s, for which no disease-modifying treatments are available to date.

One physical exercise session promotes recognition learning in rats with cognitive deficits related to amyloid beta neurotoxicity

Alzheimer’s disease is a progressive neurodegenerative pathological process that causes memory loss and cognitive impairment. One of the pathological characteristics of Alzheimer’s disease is the amyloid-β protein aggregation on the brain. The regular practice of physical exercise is a consolidated strategy on the prevention of cognitive deficits; however, little is known about the effects of acute exercise on memory. We hypothesize that one physical exercise session could act as a modulator of learning. Here we investigated the effects of one single session of running (aerobic) or strength (anaerobic) exercise on memory deficits related to neurotoxicity induced by amyloid-β. Male Wistar rats were submitted to stereotaxic surgery to intrahippocampal infusion of amyloid-β protein or saline (control). Ten days after the surgery the rats were submitted to the object recognition (OR) memory task. Immediately after the OR learning session, some rats were submitted to one treadmill running or strength exercise session. Then, the animals were submitted to memory tests 24 h, 7, and 14 days after the OR learning. We demonstrated that one physical exercise session, both aerobic as anaerobic, performed after learning improves learning and memory, promoting memory persistence in control rats and memory consolidation in rats submitted to amyloid-β neurotoxicity model. Notably, the effects of the aerobic exercise session seem to be more prominent, since they also reflect in an improvement of object discrimination index for 7 days in control animals. We verified that the mechanisms involved in the effects of aerobic exercise include the dopaminergic system activation. The mechanisms involved in the anaerobic exercise effects seem to be others since no alterations on hippocampal dopamine or noradrenaline levels were detected.

Enhancement of Amyloid β1-43 Production in the Lens Epithelium of Japanese Type 2 Diabetic Patients.

We investigated whether the accumulation of amyloid β-protein (Aβ) is enhanced in the lenses of diabetic patients. Lens epithelium samples were collected from Japanese patients during cataract surgery, and the Aβ levels and gene expression of Aβ-producing and -degrading enzymes in the samples were measured by ELISA and real-time RT-PCR, respectively. The Aβ1–43 levels in lenses of non-diabetic patients were low (0.11 pmol/g protein), while the levels in lenses of diabetic patients were significantly (6-fold) higher. Moreover, the Aβ1–43/total-Aβ ratio in the lenses of diabetic patients was also significantly higher than non-diabetic patients (p < 0.05). In addition, the mRNA levels for Aβ-producing enzymes were also enhanced in the lenses of diabetic patients. In contrast to the results for Aβ-producing enzymes, the mRNAs for the Aβ-degrading enzymes in the lenses of diabetic patients were significantly lower than in non-diabetic patients (p < 0.05). Furthermore, Aβ1–43/total-Aβ ratio in lenses was found to increase with plasma glucose level. In conclusion, these results suggest that high glucose levels cause both an increase in Aβ production and a decrease in Aβ degradation, and these changes lead to the enhancement in Aβ1–43 accumulation in the lenses of diabetic patients. These findings are useful for developing therapies for diabetic cataracts and for developing anti-cataract drugs.

Near-Infrared Light-Powered Janus Nanomotor Significantly Facilitates Inhibition of Amyloid-β Fibrillogenesis.

Inspired by the natural motors, artificial nanomotors (NMs) have emerged as intelligent, advanced, and multifunctional nanoplatforms that can perform complex tasks in living environments. However, the functionalization of these fantastic materials is in its infancy, hindering the success of this booming field. Herein, an inhibitor-conjugated near-infrared (NIR) laser-propelled Janus nanomotor (JNM-I) was constructed and first applied in the modulation of amyloid-β protein (Aβ) aggregation which is highly associated with Alzheimer's disease (AD). Under NIR light illumination, JNM-I exhibited efficient propulsion through the "self-thermophoresis" effect, and the active motion of JNM-I increased the opportunity of the contacts between the immobilized inhibitors and Aβ species, leading to an intensification of JNM-I on modulating the on-pathway Aβ aggregation, as evidenced by the distinct changes of the amyloid morphology, conformation, and cytotoxicity. For example, with a NIR irradiation, 200 μg/mL of JNM-I increased the cultured SH-SY5Y cell viability from 68% to nearly 100%, but it only protected the cells to 89% viability without an NIR irradiation. Meanwhile, the NIR irradiation effectively improved the blood-brain barrier (BBB) penetration of JNM-I. Such a JNM-I has connected artificial nanomotors with protein aggregation and provided new insight into the potential applications of various nanomotors in the prevention and treatment of AD.

Gene-specific treatment approaches in Alzheimer's disease and other tauopathies

The pathological hallmarks of Alzheimer's disease are aggregation and accumulation of amyloid-β and tau proteins. So far most interventional studies have focused on the removal of the toxic protein products, such as antibody-based immunotherapies targeted against amyloid-β and tau proteins; however, the development of gene therapies targeting gene products involved in the disease has opened up new therapeutic strategies to reduce the development of toxic protein aggregates by inhibiting the translation of pathological Alzheimer genes using antisense oligonucleotides (ASO). This has a timely influence on development of the disease. This article gives an overview of new advances in ASO-based treatment strategies for Alzheimer's disease.

Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ42 Oligomers and Protect Synapses.

Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ42) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ42 oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs. fibrils on synapses and protection by Aβ-phagocytic macrophages. We found that cortical neurons were more susceptible to Aβ42 oligomers than fibrils, triggering additional neuritic arborization retraction, functional alterations (hyperactivity and spike waveform), and loss of VGluT1- and PSD95-excitatory synapses. Co-culturing neurons with bone marrow-derived macrophages protected synapses against Aβ42 fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased Aβ42 removal by macrophages, amplified by GA stimulation: fibrils were largely cleared through intracellular CD36/EEA1+-early endosomal proteolysis, while oligomers were primarily removed via extracellular/MMP-9 enzymatic degradation. In vivo studies in GA-immunized or CD115+-monocyte-grafted APPSWE/PS1ΔE9-transgenic mice followed by pre- and postsynaptic analyses of entorhinal cortex and hippocampal substructures corroborated our in vitro findings of macrophage-mediated synaptic preservation. Together, our data demonstrate that activated macrophages effectively clear Aβ42 oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD.

Autophagy modulates Aβ accumulation and formation of aggregates in yeast

Intracellular accumulation of amyloid-β protein (Aβ) is an early event in Alzheimer's disease (AD). The autophagy-lysosomal pathway is an important pathway for maintaining cellular proteostasis and for the removal of damaged organelles and protein aggregates in all eukaryotes. Despite mounting evidence showing that modulating autophagy promotes clearance of Aβ aggregates, the regulatory mechanisms and signalling pathways underlying this process remain poorly understood. In order to gain better insight we used our previously characterised yeast model expressing GFP-Aβ42 to identify genes that regulate the removal of Aβ42 aggregates by autophagy. We report that GFP-Aβ42 is sequestered and is selectively transported to vacuole for degradation and that autophagy is the prominent pathway for clearance of aggregates. Next, to identify genes that selectively promote the removal of Aβ42 aggregates, we screened levels of GFP-Aβ42 and non-aggregating GFP-Aβ42 (19:34) proteins in a panel of 192 autophagy mutants lacking genes involved in regulation and initiation of the pathway, cargo selection and degradation processes. The nutrient and stress signalling genes RRD1, SNF4, GCN4 and SSE1 were identified. Deletion of these genes impaired GFP-Aβ42 clearance and their overexpression reduced GFP-Aβ42 levels in yeast. Overall, our findings identify a novel role for these nutrient and stress signalling genes in the targeted elimination of Aβ42 aggregates, which offer a promising avenue for developing autophagy based therapies to suppress amyloid deposition in AD.