Amyloid Aβ Research Articles

Protective effect of Lactococcus laudensis and Pediococcus parvulus against neuropathy due to amyloid-beta in Caenorhabditis elegans

In Alzheimer’s disease (AD), the amyloid-β (Aβ) protein begins to accumulate in the brain 20 years prior to any dementia symptoms manifestation, in which Aβ aggregates in the brain, causing destruction of nerve cells and resulting in memory impairments. Lifestyle and diet appear to inhibit Aβ production and amyloid deposition. Therefore, identifying factors that prevent Aβ production and administering them before the onset of AD, may be an effective preventive method. Lactic acid bacteria (LAB) exhibit various health effects on the host and are expected to have protective effects on neurological functions via brain-gut correlation. However, the protective effects of LAB against Aβ are not well understood. We investigated whether LAB feeding could ameliorate the toxicity of Aβ peptide accumulation in transgenic Caenorhabditis elegans expressing the human Aβ peptide in neurons or muscle as an AD model. Aβ expressed in muscle caused myopathy and worm paralysis, while Aβ in neurons disturbed chemotactic activity. Among 14 screened strains, Lactococcus laudensis (LL) and Pediococcus parvulus (PP) prevented the AD worms from losing their chemotaxis behavior and becoming paralyzed by the Aβ peptide. Immunostaining and western blotting indicated that Aβ peptide was significantly suppressed in worms fed these two strains, and binding of the Aβ to vitellogenin was particularly inhibited. Conversely, the mRNA level of the Aβ gene did not change between LL- or PP-fed worms and the control. In conclusion, LL and PP alleviate neurotoxicity by inhibiting Aβ accumulation; AD model worms can be used to screen efficient LAB for AD prevention.

Willis Lecture: Biomarkers for Inflammatory White Matter Injury in Binswanger Disease Provide Pathways to Precision Medicine.

Binswanger disease is the small vessel form of vascular cognitive impairment and dementia. Deposition of Alzheimer disease proteins can begin in midlife and progress slowly, whereas aging of the vasculature also can begin in midlife, continuing to progress into old age, making mixed dementia the most common type of dementia. Biomarkers facilitate the early diagnosis of dementias. It is possible to diagnose mixed dementia before autopsy with biomarkers for vascular disease derived from diffusor tensor images on magnetic resonance imaging and Alzheimer disease proteins, Aβ (amyloid β), and phosphorylated tau, in cerebrospinal fluid or in brain with positron emission tomography. The presence of vascular disease accelerates cognitive decline. Both misfolded proteins and vascular disease promote inflammation, which can be detected in cerebrospinal fluid by the presence of MMPs (matrix metalloproteinases), angiogenic growth factors, and cytokines. MMPs disrupt the blood-brain barrier and break down myelin, producing Binswanger disease's 2 main pathological features. Advances in detecting biomarkers in plasma will provide early detection of dementia and aided by machine learning and artificial intelligence, will enhance diagnosis and form the basis for early treatments.

Design and synthesis of new indole drug candidates to treat Alzheimer’s disease and targeting neuro-inflammation using a multi-target-directed ligand (MTDL) strategy

A novel series of indole-based compounds was designed, synthesised, and evaluated as anti-Alzheimer’s and anti-neuroinflammatory agents. The designed compounds were in vitro evaluated for their AChE and BuChE inhibitory activities. The obtained results revealed that compound 3c had higher selectivity for AChE than BuChE, while, 4a, 4b, and 4d showed selectivity for BuChE over AChE. Compounds 5b, 6b, 7c, and 10b exerted dual AChE/BuChE inhibitory activities at nanomolar range. Compounds 5b and 6b had the ability to inhibit the self-induced Aβ amyloid aggregation. Different anti-inflammatory mediators (NO, COX-2, IL-1β, and TNF-α) were assessed for compounds 5b and 6b. Cytotoxic effect of 5b and 6b against human neuroblastoma (SH-SY5Y) and normal hepatic (THLE2) cell lines was screened in vitro. Molecular docking study inside rhAChE and hBuChE active sites, drug-likeness, and ADMET prediction were performed.

Cu and Zn Interactions with Peptides Revealed by High-Resolution Mass Spectrometry.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by abnormal extracellular amyloid-beta (Aβ) peptide depositions in the brain. Among amorphous aggregates, altered metal homeostasis is considered a common risk factor for neurodegeneration known to accelerate plaque formation. Recently, peptide-based drugs capable of inhibiting amyloid aggregation have achieved unprecedented scientific and pharmaceutical interest. In response to metal ions binding to Aβ peptide, metal chelation was also proposed as a therapy in AD. The present study analyzes the interactions formed between NAP octapeptide, derived from activity-dependent neuroprotective protein (ADNP), amyloid Aβ(9–16) fragment and divalent metal ions such as Cu and Zn. The binding affinity studies for Cu and Zn ions of synthetic NAP peptide and Aβ(9–16) fragment were investigated by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), electrospray ion trap mass spectrometry (ESI-MS) and atomic force microscopy (AFM). Both mass spectrometric methods confirmed the formation of metal–peptide complexes while the AFM technique provided morphological and topographic information regarding the influence of metal ions upon peptide crystallization. Our findings showed that due to a rich histidine center, the Aβ(9–16) fragment is capable of binding metal ions, thus becoming stiff and promoting aggregation of the entire amyloid peptide. Apart from this, the protective effect of the NAP peptide was found to rely on the ability of this octapeptide to generate both chelating properties with metals and interactions with Aβ peptide, thus stopping its folding process.

Complement component 3 and complement factor H protein levels are altered in brain tissues from people with human immunodeficiency virus: A pilot study.

People with HIV (PWH) continue to suffer from dysfunction of the central nervous system, as evidenced by HIV-associated neurocognitive disorder (HAND), despite antiretroviral therapy and suppressed viral loads. As PWH live longer they may also be at risk of age-related neurodegenerative diseases such Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). The complement system is associated with deposition of AD-related proteins such as beta amyloid (Aβ), neuroinflammation, and neurological dysfunction in PWH. Complement component 3 (C3) is a key protagonist in the complement cascade and complement factor H (CFH) is an antagonist of C3 activity. We investigated the relationship between C3 and CFH levels in the brain and Aβ plaques and neurological dysfunction in 22 PWH. We analyzed by immunoblot C3 and CFH protein levels in frontal cortex (FC) and cerebellum (CB) brain specimens from PWH previously characterized for Aβ plaque deposition. C3 and CFH protein levels were then correlated with specific cognitive domains. C3 protein levels in the FC were significantly increased in brains with Aβ plaques and in brains with HAND compared to controls. In the CB, C3 levels trended higher in brains with Aβ plaques. Overall C3 protein levels were significantly higher in the FC compared to the CB, but the opposite was true for CFH, having significantly higher levels of CFH protein in the CB compared to the FC. However, only CFH in the FC showed significant correlations with specific domains, executive function and motor performance. These findings corroborate previous results showing that complement system proteins are associated with HAND and AD neuropathogenesis.

Alzheimer's Disease Severity Is Associated with an Imbalance in Serum Levels of Enzymes Regulating Plasmin Synthesis.

Alzheimer’s disease (AD) is a central nervous system (CNS) disease characterized by loss of memory, cognitive functions, and neurodegeneration. Plasmin is an enzyme degrading many plasma proteins. In the CNS, plasmin may reduce the accumulation of beta amyloid (Aβ) and have other actions relevant to AD pathophysiology. Brain plasmin synthesis is regulated by two enzymes: one activating, the tissue plasminogen activator (tPA), and the other inhibiting, the plasminogen activator inhibitor-1 (PAI-1). We investigated the levels of tPA and PAI-1 in serum from 40 AD and 40 amnestic mild cognitively impaired (aMCI) patients compared to 10 cognitively healthy controls. Moreover, we also examined the PAI-1/tPA ratio in these patient groups. Venous blood was collected and the PAI-1 and tPA serum concentrations were quantified using sandwich ELISAs. The results showed that PAI-1 levels increased in AD and aMCI patients. This increase negatively correlated with cognitive performance measured using the Mini-Mental Status Exam (MMSE). Similarly, the ratio between tPA and PAI-1 gradually increases in aMCI and AD patients. This study demonstrates that AD and aMCI patients have altered PAI-1 serum levels and PAI-1/tPA ratio. Since these enzymes are CNS regulators of plasmin, PAI-1 serum levels could be a marker reflecting cognitive decline in AD.

Designed peptides as nanomolar cross-amyloid inhibitors acting via supramolecular nanofiber co-assembly

Amyloid self-assembly is linked to numerous devastating cell-degenerative diseases. However, designing inhibitors of this pathogenic process remains a major challenge. Cross-interactions between amyloid-β peptide (Aβ) and islet amyloid polypeptide (IAPP), key polypeptides of Alzheimer’s disease (AD) and type 2 diabetes (T2D), have been suggested to link AD with T2D pathogenesis. Here, we show that constrained peptides designed to mimic the Aβ amyloid core (ACMs) are nanomolar cross-amyloid inhibitors of both IAPP and Aβ42 and effectively suppress reciprocal cross-seeding. Remarkably, ACMs act by co-assembling with IAPP or Aβ42 into amyloid fibril-resembling but non-toxic nanofibers and their highly ordered superstructures. Co-assembled nanofibers exhibit various potentially beneficial features including thermolability, proteolytic degradability, and effective cellular clearance which are reminiscent of labile/reversible functional amyloids. ACMs are thus promising leads for potent anti-amyloid drugs in both T2D and AD while the supramolecular nanofiber co-assemblies should inform the design of novel functional (hetero-)amyloid-based nanomaterials for biomedical/biotechnological applications.

The Possible Mechanism of Amyloid Transformation Based on the Geometrical Parameters of Early-Stage Intermediate in Silico Model for Protein Folding.

The specificity of the available experimentally determined structures of amyloid forms is expressed primarily by the two- and not three-dimensional forms of a single polypeptide chain. Such a flat structure is possible due to the β structure, which occurs predominantly. The stabilization of the fibril in this structure is achieved due to the presence of the numerous hydrogen bonds between the adjacent chains. Together with the different forms of twists created by the single R- or L-handed α-helices, they form the hydrogen bond network. The specificity of the arrangement of these hydrogen bonds lies in their joint orientation in a system perpendicular to the plane formed by the chain and parallel to the fibril axis. The present work proposes the possible mechanism for obtaining such a structure based on the geometric characterization of the polypeptide chain constituting the basis of our early intermediate model for protein folding introduced formerly. This model, being the conformational subspace of Ramachandran plot (the ellipse path), was developed on the basis of the backbone conformation, with the side-chain interactions excluded. Our proposal is also based on the results from molecular dynamics available in the literature leading to the unfolding of α-helical sections, resulting in the β-structural forms. Both techniques used provide a similar suggestion in a search for a mechanism of conformational changes leading to a formation of the amyloid form. The potential mechanism of amyloid transformation is presented here using the fragment of the transthyretin as well as amyloid Aβ.

Cathepsin B-A Neuronal Death Mediator in Alzheimer's Disease Leading to Neurodegeneration.

The lysosomal cysteine protease enzyme, named Cathepsin B, mainly degrades the protein and manages its average turnover in our body. The Cathepsin B active form is mostly present inside the lysosomal part at a cellular level, providing the slightly acidic medium for its activation. Multiple findings on Cathepsin B reveal its involvement in neurons' degeneration and a possible role as a neuronal death mediator in several neurodegenerative diseases. In this review article, we highlight the participation of Cathepsin B in the etiology/progress of AD, along with various other factors. The enzyme is involved in producing neurotoxic Aβ amyloid in the AD brain by acting as the β-secretase enzyme in the regulated secretory pathways responsible for APP processing. Aβ amyloid accumulation and amyloid plaque formation lead to neuronal degeneration, one of the prominent pathological hallmarks of AD. Cathepsin B is also involved in the production of PGlu-Aβ, which is a truncated and highly neurotoxic form of Aβ. Some of the findings also revealed that Cathepsin B specific gene deletion decreases the level of PGlu-Aβ inside the brain of experimental mice. Therefore, neurotoxicity might be considered a new pathological indication of AD due to the involvement of Cathepsin B. It also damages neurons present in the CNS region by producing inflammatory responses and generating mitochondrial ROS. However, Cathepsin B inhibitors, i.e., CA-074, can prevent neuronal death in AD patients. The other natural inhibitors are also equally effective against neuronal damage with higher selectivity. Its synthetic inhibitors are specific for their target; however, they lose their selectivity in the presence of quite a few reducing agents. Therefore, a humanized monoclonal antibody is used as a selective Cathepsin B inhibitor to overcome the problem experienced. The use of Cathepsin B for the treatment of AD and other neurodegenerative diseases could be considered a rational therapeutic target.

Proteomic Discovery and Validation of Novel Fluid Biomarkers for Improved Patient Selection and Prediction of Clinical Outcomes in Alzheimer's Disease Patient Cohorts.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by progressive cognitive decline. The two cardinal neuropathological hallmarks of AD include the buildup of cerebral β amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. The current disease-modifying treatments are still not effective enough to lower the rate of cognitive decline. There is an urgent need to identify early detection and disease progression biomarkers that can facilitate AD drug development. The current established readouts based on the expression levels of amyloid beta, tau, and phospho-tau have shown many discrepancies in patient samples when linked to disease progression. There is an urgent need to identify diagnostic and disease progression biomarkers from blood, cerebrospinal fluid (CSF), or other biofluids that can facilitate the early detection of the disease and provide pharmacodynamic readouts for new drugs being tested in clinical trials. Advances in proteomic approaches using state-of-the-art mass spectrometry are now being increasingly applied to study AD disease mechanisms and identify drug targets and novel disease biomarkers. In this report, we describe the application of quantitative proteomic approaches for understanding AD pathophysiology, summarize the current knowledge gained from proteomic investigations of AD, and discuss the development and validation of new predictive and diagnostic disease biomarkers.

α-Enolase reduces cerebrovascular Aβ deposits by protecting Aβ amyloid formation.

Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid β (Aβ) deposits and causes dementia and cerebral hemorrhage. Although α-enolase (ENO1) was shown to possess multifunctional roles, its exact functions in CAA pathogenesis have not been determined. In this study, we focused on ENO1, a well-known glycolytic enzyme, which was previously identified via a proteomic approach as an upregulated protein in brain samples from patients with Alzheimer's disease (AD). We utilized the thioflavin T fluorescence assay and transmission electron microscopy to monitor the effects of ENO1 on amyloid formation by Aβ peptides. We also cultured murine primary cerebrovascular smooth muscle cells to determine the effects of ENO1 on Aβ cytotoxicity. To investigate the effects of ENO1 in vivo, we infused ENO1 or a vehicle control into the brains of APP23 mice, atransgenicmodelofAD/CAA, using a continuous infusion system, followed by a cognitive test and pathological and biochemical analyses. We found that novel functions of ENO1 included interacting with Aβ and inhibiting its fibril formation, disrupting Aβ fibrils, and weakening the cytotoxic effects of these fibrils via proteolytic degradation of Aβ peptide. We also demonstrated that infusion of ENO1 into APP23 mouse brains reduced cerebrovascular Aβ deposits and improved cognitive impairment. In addition, we found that enzymatically inactivated ENO1 failed to inhibit Aβ fibril formation and fibril disruption. The proteolytic activity of ENO1 may thus underlie the enzyme's cytoprotective effect and clearance of Aβ from the brain, and ENO1 may be a therapeutic target in CAA.

The Mechanistic Pathways of Periodontal Pathogens Entering the Brain: The Potential Role of Treponema denticola in Tracing Alzheimer's Disease Pathology.

Alzheimer’s Disease (AD) is a complex neurodegenerative disease and remains the most common form of dementia. The pathological features include amyloid (Aβ) accumulation, neurofibrillary tangles (NFTs), neural and synaptic loss, microglial cell activation, and an increased blood–brain barrier permeability. One longstanding hypothesis suggests that a microbial etiology is key to AD initiation. Among the various periodontal microorganisms, Porphyromonas gingivalis has been considered the keystone agent to potentially correlate with AD, due to its influence on systemic inflammation. P. gingivalis together with Treponema denticola and Tannerella forsythia belong to the red complex consortium of bacteria advocated to sustain periodontitis within a local dysbiosis and a host response alteration. Since the implication of P. gingivalis in the pathogenesis of AD, evidence has emerged of T. denticola clusters in some AD brain tissue sections. This narrative review explored the potential mode of spirochetes entry into the AD brain for tracing pathology. Spirochetes are slow-growing bacteria, which can hide within ganglia for many years. It is this feature in combination with the ability of these bacteria to evade the hosts’ immune responses that may account for a long lag phase between infection and plausible AD disease symptoms. As the locus coeruleus has direct connection between the trigeminal nuclei to periodontal free nerve endings and proprioceptors with the central nervous system, it is plausible that they could initiate AD pathology from this anatomical region.

Conformational Variability of Amyloid-β and the Morphological Diversity of Its Aggregates.

Protein folding is the most fundamental and universal example of biomolecular self-organization and is characterized as an intramolecular process. In contrast, amyloidogenic proteins can interact with one another, leading to protein aggregation. The energy landscape of amyloid fibril formation is characterized by many minima for different competing low-energy structures and, therefore, is much more enigmatic than that of multiple folding pathways. Thus, to understand the entire energy landscape of protein aggregation, it is important to elucidate the full picture of conformational changes and polymorphisms of amyloidogenic proteins. This review provides an overview of the conformational diversity of amyloid-β (Aβ) characterized from experimental and theoretical approaches. Aβ exhibits a high degree of conformational variability upon transiently interacting with various binding molecules in an unstructured conformation in a solution, forming an α-helical intermediate conformation on the membrane and undergoing a structural transition to the β-conformation of amyloid fibrils. This review also outlines the structural polymorphism of Aβ amyloid fibrils depending on environmental factors. A comprehensive understanding of the energy landscape of amyloid formation considering various environmental factors will promote drug discovery and therapeutic strategies by controlling the fibril formation pathway and targeting the consequent morphology of aggregated structures.

Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer’s disease

Alzheimer’s disease (AD) is complex and highly heterogeneous. Less than 10% of AD cases are early-onset (EOAD) caused by autosomal dominantly inherited mutations in amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2), each of which can increase Aβ generation and, thus, amyloid plaques. The remaining 90% of cases of AD are late-onset (LOAD) or sporadic. Intense research efforts have led to identification of many genes that increase the risk of AD. An IQ motif containing protein K (IQCK) was recently identified by several investigators as an Alzheimer’s disease risk gene. However, how IQCK increases AD risk is completely unknown. Since IQCK is a novel gene, there is limited information on its physiological characterization. To understand its role in AD, it is first important to determine its subcellular localization, whether and where it is expressed in the brain, and what type of brain cells express the IQCK protein. Therefore, in this study, we show by immunocytochemical (ICC) staining that IQCK is expressed in both the nucleus and the cytoplasm of SH-SY5Y neuroblastoma cells as well as HeLa cells but not in either HMC3 microglial or CHO cells. By immunohistochemistry (IHC), we also show that IQCK is expressed in both mouse and human neurons, including neuronal processes in vivo in the mouse brain. IHC data also show that the IQCK protein is widely expressed throughout the mouse brain, although regional differences were noted. IQCK expression was highest in the brainstem (BS), followed by the cerebellum (CB) and the cortex (CX), and it was lowest in the hippocampus (HP). This finding was consistent with data from an immunoblot analysis of brain tissue homogenates. Interestingly, we found IQCK expression in neurons, astrocytes, and oligodendrocytes using cell-specific antibodies, but IQCK was not detected in microglial cells, consistent with negative in vitro results in HMC3 cells. Most importantly, we found that actin-normalized IQCK protein levels were increased by 2 folds in AD brains relative to normal control (NC) brains. Furthermore, the IQCK protein was found in amyloid plaques, suggesting that IQCK may play a pathogenic role in either Aβ generation or amyloid plaque deposition in AD.

Interaction Interface of Aβ42 with Human Na,K-ATPase Studied by MD and ITC and Inhibitor Screening by MD.

Alzheimer’s disease (AD) is a neurodegenerative disease accompanied by progressive cognitive and memory dysfunction due to disruption of normal electrotonic properties of neurons and neuronal loss. The Na,K-ATPase interaction with beta amyloid (Aβ) plays an important role in AD pathogenesis. It has been shown that Na,K-ATPase activity in the AD brain was significantly lower than those in age-matched control brain. The interaction of Aβ42 with Na,K-ATPase and subsequent oligomerization leads to inhibition of the enzyme activity. In this study interaction interfaces between three common Aβ42 isoforms, and different conformations of human Na,K-ATPase (α1β1) have been obtained using molecular modeling, including docking and molecular dynamics (MD). Interaction sites of Na,K-ATPase with Aβ42 are localized between extracellular parts of α- and β- subunits and are practically identical for Na,K-ATPase at different conformations. Thermodynamic parameters for the formation of Na,K-ATPase:Aβ42 complex at different conformations acquired by isothermal titration calorimetry (ITC) are similar, which is in line with the data of molecular modeling. Similarity of Na,K-ATPase interaction interfaces with Aβ in all conformations allowed us to cross-screen potential inhibitors for this interaction and find pharmaceutical compounds that could block it.

Functionalized Allopurinols Targeting Amyloid-Binding Alcohol Dehydrogenase Rescue Aβ-Induced Mitochondrial Dysfunction.

Alzheimer's disease (AD) is the most common dementia affecting one in nine people over 65. Only a handful of small-molecule drugs and the anti-β amyloid (Aβ) antibody aducanumab are approved to treat AD. However, they only serve to reduce symptoms of advanced disease. Novel treatments administered early in disease progression before the accumulation of Aβ and tau reaches the threshold where neuroinflammation is triggered and irreversible neuronal damage occurs are more likely to provide effective therapy. There is a growing body of evidence implying that mitochondrial dysfunction occurs at an early stage of AD pathology. The mitochondrial enzyme amyloid-binding alcohol dehydrogenase (ABAD) binds to Aβ potentiating toxicity. Moreover, ABAD has been shown to be overexpressed in the same areas of the brain most affected by AD. Inhibiting the Aβ-ABAD protein-protein interaction without adversely affecting normal enzyme turnover is hypothesized to be a potential treatment strategy for AD. Herein, we conduct structure-activity relationship studies across a series of functionalized allopurinol derivatives to determine their ability to inhibit Aβ-mediated reduction of estradiol production from ABAD. The lead compound resulting from these studies possesses potent activity with no toxicity up to 100 μM, and demonstrates an ability to rescue defective mitochondrial metabolism in human SH-SY5Y cells and rescue both defective mitochondrial metabolism and morphology ex vivo in primary 5XFAD AD mouse model neurons.

Peptide-Modified Gemini Surfactants as Delivery System Building Blocks with Dual Functionalities for Glaucoma Treatment: Gene Carriers and Amyloid-Beta (Aβ) Self-Aggregation Inhibitors.

Retinal ganglion cell (RGC) neurodegeneration in glaucoma has potential links with amyloid-β (Aβ) deposition. Targeting the Aβ pathway was shown to reduce RGC apoptosis and protect RGCs from degeneration. We report exploratory studies on the amyloid Aβ40 aggregation inhibition properties of four cell adhesion peptide (CAP)-gemini surfactants that are intended as building blocks for gene carrier nanoparticles for glaucoma treatment. The CAP-gemini surfactants (18-7N(p1-4)-18) were evaluated as potential Aβ40 peptide aggregation inhibitors by a fluorescence kinetic assay and for their binding interactions with Aβ40 dimers by molecular docking studies. In vitro Aβ40 peptide aggregation inhibition studies showed that the 18-7N(p3)-18 and 18-7N(p1)-18 ligands inhibit Aβ40 peptide aggregation and prevent the formation of higher order structures. CDOCKER energies and CDOCKER interaction energies demonstrated that the CAP-gemini surfactants formed more stable complexes in the Aβ40 dimer assembly and underwent both polar and nonpolar interactions compared to CAP peptides alone. Also, 18-7N(p3)-18 showed a significantly lower CDOCKER energy compared to that of the unmodified gemini surfactant 18-7NH-18 (p < 0.0001) and 18-7N(p4)-18 (p < 0.001), 18-7N(p1)-18, and 18-7N(p2)-18. Similarly, 18-7N(p3)-18 showed a significantly lower CDOCKER interaction energy compared to that of 18-7NH-18, 18-7N(p4)-18 (p < 0.0001), and 18-7N(p2)-18 (p < 0.001), while 18-7N(p3)-18 and 18-7N(p1)-18 showed similar CDOCKER interaction energies. These studies suggest that a combination of both hydrophobic and electrostatic interactions contributes to the anti-Aβ40 aggregation activity of CAP-gemini surfactants. CAP-gemini surfactants showed 10-fold better Aβ40 peptide aggregation inhibition compared to previously reported values and could provide a new opportunity for glaucoma treatment as dual-functional gene carriers.

Amyloid-β aggregates induced by β-cholesteryl glucose-embedded liposomes

Senile plaques that is characterized as an amyloid deposition found in Alzheimer's disease are composed primarily of fibrils of an aggregated peptide, amyloid β (Aβ). The ability to monitor senile plaque formation on a neuronal membrane under physiological conditions provides an attractive model. In this study, the growth behavior of amyloid Aβ fibrils in the presence of liposomes incorporating β-cholesteryl-D-glucose (β-CG) was examined using total internal reflection fluorescence microscopy, transmittance electron microscopy, and other spectroscopic methods. We found that β-CG on the liposome membrane induced the spontaneous formation of spherulitic Aβ fibrillar aggregates. The β-CG cluster formed on liposome membranes appeared to induce the accumulation of Aβ, followed by the growth of the spherulitic Aβ aggregates. In contrast, DMPC and DMPC incorporated cholesterol-induced fibrils that are laterally associated with each other. A comparison study using three types of liposomes implied that the induction of glucose contributed to the agglomeration of Aβ fibrils and liposomes. This agglomeration required the spontaneous formation of spherulitic Aβ fibrillary aggregates. This action can be regarded as a counterbalance to the growth of fibrils and their toxicity, which has great potential in the study of amyloidopathies.

Electroacupuncture improves learning-memory ability by down-regulating expression of hippocampal Aβ1-42 and Tau and NF-κB proteins in diabetic rats with cognitive impairment

To observe the effect of electroacupuncture(EA) on the expression of nuclear transcription factors κB (NF-κB) and Tau protein and content of amyloid (Aβ) in diabetic rats with cognitive impairment, so as to explore its mechanism underlying improvement of learning-memory ability. Male SD rats were randomly divided into normal control (n=9), model (n=9) and EA (n=9) groups. The diabetic mellitus model was established by feeding the rats with high fat and high sugar for 1 month and intraperitoneal injection of STZ (25 mg·kg-1·d-1) for 2 days. EA was applied to "Zusanli"(ST36) and "Neiting"(ST44) for 20 min, alternatively on both side every day, and "Yishu"(EX-B3) was stimulated by twirling the acupuncture needle with uniform reinforcing-reducing method for 1 min, followed by retaining it for 20 min. The treatment was conducted 6 times a week for 4 weeks. The learning-memory ability was evaluated by using Morris water maze swimming test. The blood glucose level was randomly detected by using a glucometer, the content of Aβ1-42 in the hippocampal tissue was detected by ELISA, and the relative expression levels of hippocampal Tau and NF-κB p65 proteins and mRNAs were determined by Western blot and fluorescence quantitative real-time PCR, separately. After modeling, the blood glucose, escape latency, Aβ1-42 content and the expression levels of Tau and NF-κB p65 proteins and mRNAs in the model group were significantly increased (P<0.01, P<0.05) in comparison with the normal control group. Following EA intervention, the modeling induced increase of blood glucose, escape latency, Aβ1-42 content and the expression levels of Tau and NF-κB p65 proteins and mRNAs were reversed (P<0.05, P<0.01). EA can improve the learning-memory ability in rats with diabetic cognitive impairment, which may be related to its function in down-regulating the levels of hippocampal Aβ1-42, Tau and NF-κB proteins.

The Influence of 24-h Ambulatory Blood Pressure on Cognitive Function and Neuropathological Biomarker in Patients With Alzheimer's Disease.

PurposeThis study aimed to investigate the influence of 24-h ambulatory blood pressure (BP) on cognitive function and neuropathological biomarkers in patients with Alzheimer's disease (AD) at the stages of mild cognitive impairment (MCI) and dementia.MethodsThe patients with AD were divided into the MCI (AD-MCI) group and the dementia (AD-D) group. Notably, 24-h BP variables, including BP level, coefficient of variation (CV) of BP, and pulse pressure, were collected and compared between the two groups. The correlations between 24-h BP variables and the scores of cognitive domains were analyzed. The independent influencing factors of cognitive domains of patients with AD were investigated. The levels of neuropathological biomarkers of AD, including β amyloid (Aβ)1−42, phosphorylated tau (P-tau), and total tau (T-tau), in cerebrospinal fluid (CSF) were measured and compared between the two groups, and the correlations between 24-h BP variables and the levels of neuropathological biomarkers of AD were analyzed.ResultsDaytime CV of systolic BP (SBP) was significantly increased in the AD-D group compared to that in the AD-MCI group. The 24-h and daytime CV of SBP and ambulatory pulse pressure were significantly and negatively correlated with memory score. The average 24-h and average daytime SBP level and CV of SBP, daytime CV of diastolic BP (DBP), and 24-h, daytime, and night-time ambulatory pulse pressure were significantly and negatively correlated with language score. The average 24-h SBP level, daytime CV of SBP, and 24-h, daytime, and night-time ambulatory pulse pressure were significantly and negatively correlated with attention score. Further analysis indicated that daytime CV of SBP as well as age and course of disease were the independent influencing factors of language. Age was also the independent influencing factor of memory and attention of patients with AD. T-tau level in CSF in the AD-D group was significantly higher than that in the AD-MCI group, but the levels of Aβ1−42, P-tau, and T-tau in CSF were not correlated with 24-h ambulatory BP variables.ConclusionDaytime CV of SBP was the independent influencing factor of language in patients with AD. The AD-D patients had significantly severe neurodegeneration than AD-MCI patients, which was, however, not through the influence of 24-h ambulatory BP variables on neuropathological biomarkers of AD.