Interaction Of Aβ Research Articles

Suppressive Effects of Beta Amyloid Peptides (1-42) and (25-35) on Kv1.1 Channel Activity

Beta amyloid (Aβ) peptides have long been implicated in Alzheimer's Disease (AD) pathology, linking them to disruption of: Ca2+ homeostasis, synaptic communication, and long-term potentiation (LTP). But the mechanism(s) underlying these effects are still unclear. Because Kv1.1 and related channels are activated during an action potential, regulate depolarization-produced Ca2+ influx, and inhibition of Kv1 channels can be neurotoxic, we speculate that Aβ-suppression of Kv1 channels may be an early event in AD pathogenesis. Using murine Kv1.1 channels expressed in Xenopus oocytes, we have observed the effects of Aβ(1-42) and the “core” peptide (25-35) on both macro- and micro-scopic currents. Both the bath application of Aβ(1-42) and Aβ(25-35) produced 40-50% suppression of macroscopic Kv1.1 current within 30 m. Suppression of Kv1.1 by Aβ(1-42) was partially dependent on intracellular Ca2+ and PP2B, showing only ∼25% reduction when cells were loaded with BAPTA-AM or exposed to the PP2B-inhibitor cyclosporine A (CsA). Patch-clamp results suggested that Aβ-suppression of Kv1.1 involved both PP2B-dephosphorylation and direct protein-protein interaction of Aβ with Kv1.1. Exposure of the intracellular face of Kv1.1 channels in ripped-off oocyte patches to either catalytically-active PP2B, or Aβ(1-42), produced gradual reductions in p(open), followed by the abrupt disappearance of Kv1.1 activity. Using “tip-dip” artificial membrane methods, Aβ(25-35) exposure eliminated Kv1.1 channel activity when applied to the channel intracellular face. Kv1.1 channels have also been incorporated into Black Lipid Membranes (BLMs), and we are currently assessing the effects of exposure of Aβ to both intra- and extra-cellular faces of Kv1.1. Suppression of presynaptic Kv1.1 (and related) channels could lead to enhanced action potentials, thus allowing greater influx of Ca2+ and subsequent increase in glutamate release. Postsynaptically, the increased glutamate release, through activation of AMPA and NMDA receptors, may contribute to excitotoxicity.

Measuring longitudinal cognition: Individual tests versus composites

IntroductionLongitudinal cohort studies of cognitive aging must confront several sources of within-person variability in scores. In this article, we compare several neuropsychological measures in terms of longitudinal error variance and relationships with biomarker-assessed brain amyloidosis (Aβ). MethodsAnalyses used data from the Wisconsin Registry for Alzheimer's Prevention. We quantified within-person longitudinal variability and age-related trajectories for several global and domain-specific composites and their constituent scores. For a subset with cerebrospinal fluid or amyloid positron emission tomography measures, we examined how Aβ modified cognitive trajectories. ResultsGlobal and theoretically derived composites exhibited lower intraindividual variability and stronger age × Aβ interactions than did empirically derived composites or raw scores from single tests. For example, the theoretical executive function outperformed other executive function scores on both metrics. DiscussionThese results reinforce the need for careful selection of cognitive outcomes in study design, and support the emerging consensus favoring composites over single-test measures.

Cell signaling associated with internalization of 67 kDa laminin receptor (67LR) by soluble laminin and its implication for protection against neurodegenerative diseases.

Cell signaling associated with internalization of 67 kDa laminin receptor (67LR) by soluble laminin and its implication for protection against neurodegenerative diseases.

Interaction of Amyloidogenic Proteins with Membranes and Molecular Mechanism for the Development of Alzheimer’s disease

Molecular mechanism of diseases like Alzheimer's disease (AD) and Parkinson's diseases (PD) is associated with misfolding of specific proteins, such as amyloid beta (Aβ) proteins in the case of AD, followed by their self-assembly into toxic oligomers along with the formation of amyloid fibrils assembled as plaques in the brain. Interaction of Aβ with membrane can lead to membrane damage; this process is considered as the major factor associated with the AD development. Additionally, membrane can facilitate the aggregation process of Aβ proteins. This important property of membranes is discussed in this review. A specific emphasis is given to the recently discovered property of cellular membranes to catalyze the initial step of Aβ aggregation process by which self-assembly of Aβ can be observed at physiologically low concentrations of Aβ proteins. At such low concentrations, no spontaneous aggregation occurs in the bulk solution. This fact was a major weakness of the protein aggregation model for AD. The catalytic property of membrane surfaces towards Aβ aggregation depends on the membrane composition. This finding suggests a number of novel ideas on the development of treatments and preventions for AD, which is briefly discussed in the review.

Amyloid β-Peptide Interaction with Membranes: Can Chaperones Change the Fate?

The understanding of amyloid β-peptide (Aβ) interactions with cellular membranes is a crucial molecular challenge against Alzheimer's disease. Indeed, Aβ prefibrillar oligomeric intermediates are believed to be the most toxic species, able to induce cellular damagesdirectly by membrane damage. We present a neutron-scattering study on the interaction of large unilamellar vesicles (LUV), as cell membrane models, with both freshly dissolved Aβ and early toxic prefibrillar oligomers, intermediate states in the amyloid pathway. In addition, we explore the effect of coincubating the Aβ-peptide with the chaperonin Hsp60, which is known to strongly interact with it in its aggregation pattern. In fact, the interaction of the LUV with coincubated Aβ/Hsp60, right after mixing and after following the aggregation protocol leading to the toxic intermediates in the absence of Hsp60, is studied. Neutron spin echo experiments show that the interaction with both freshly dissolved and aggregate Aβ species brings about an increase in membrane stiffness, whereas the presence of even very low amounts of Hsp60 (ratio Aβ/Hsp60 = 25:1) maintains unaltered the elastic properties of the membrane bilayer. A coherent interpretation of these results, related to previous literature, can be based on the ability of the chaperonin to interfere with Aβ aggregation, by the specific recognition oftheAβ-reactive transient species. In this framework, our results strongly suggest that early in a freshly dissolved Aβ solution are presentsomespecies able to modify the bilayer dynamics, and the chaperonin plays the role of an assistant in such stochastic "misfolding events", avoiding the insult on the membrane as well as the onset of the aggregation cascade.

Analysis of β-Amyloid-induced Abnormalities on Fibrin Clot Structure by Spectroscopy and Scanning Electron Microscopy.

This article presents methods for generating in vitro fibrin clots and analyzing the effect of beta-amyloid (Aβ) protein on clot formation and structure by spectrometry and scanning electron microscopy (SEM). Aβ, which forms neurotoxic amyloid aggregates in Alzheimer's disease (AD), has been shown to interact with fibrinogen. This Aβ-fibrinogen interaction makes the fibrin clot structurally abnormal and resistant to fibrinolysis. Aβ-induced abnormalities in fibrin clotting may also contribute to cerebrovascular aspects of the AD pathology such as microinfarcts, inflammation, as well as, cerebral amyloid angiopathy (CAA). Given the potentially critical role of neurovascular deficits in AD pathology, developing compounds which can inhibit or lessen the Aβ-fibrinogen interaction has promising therapeutic value. In vitro methods by which fibrin clot formation can be easily and systematically assessed are potentially useful tools for developing therapeutic compounds. Presented here is an optimized protocol for in vitro generation of the fibrin clot, as well as analysis of the effect of Aβ and Aβ-fibrinogen interaction inhibitors. The clot turbidity assay is rapid, highly reproducible and can be used to test multiple conditions simultaneously, allowing for the screening of large numbers of Aβ-fibrinogen inhibitors. Hit compounds from this screening can be further evaluated for their ability to ameliorate Aβ-induced structural abnormalities of the fibrin clot architecture using SEM. The effectiveness of these optimized protocols is demonstrated here using TDI-2760, a recently identified Aβ-fibrinogen interaction inhibitor.

Beta-amyloid short- and long-term synaptic entanglement.

Beta-amyloid (Aβ) is a peptide that derives from the proteolytic cleavage of the amyloid precursor protein (APP) by several secretases. Since its isolation and sequencing from Alzheimer's disease (AD) brains, Aβ has been intensively investigated in the context of AD as the main pathogenic marker responsible for neurodegenerative processes. During the last three decades, results from several independent studies have converged to form the so-called amyloid cascade hypothesis of AD and several therapeutic strategies designed to modulate the APP amyloidogenic pathway have been developed. However, none of the clinical trials targeting Aβ culminated in a significant clinical outcome, thus challenging the concept that targeting Aβ, at least within the time window so far explored in clinical trials, may have a therapeutic effect. However, besides its presence in AD brains, brain cells produce Aβ, thus suggesting that, under normal conditions, the peptide may have a role in the regulation of brain functions, which is consistent with its ubiquitous presence and normal synthesis. Taking into account that Aβ has been found to exhibit a dual role strictly correlated with its concentration (neuromodulatory/neuroprotective vs neurotoxic), we discuss emerging evidence indicating that physiological concentrations of Aβ peptide modulate synaptic activity. The review examines the physiological effects of Aβ on acute synaptic activities and the functional interplay existing between Aβ and different neurotransmitter systems, i.e. cholinergic, glutamatergic, GABAergic, catecholaminergic, serotoninergic, and peptidergic. The review also provides an insight into the different mechanisms through which Aβ affects synaptic activity, focusing in particular on Aβ interaction with the key synaptic proteins that regulate the neurotransmitter release machinery. These interactions may help to identify or recognize alterations in neurotransmitter activity and correlated behaviors as predictive signs for the development of AD and to understand the limitations of current interventions and the failure so far of amyloid targeted therapies.

G82S polymorphism of receptor for advanced glycation end products gene and serum soluble RAGE levels in mild cognitive impairment and dementia of Alzheimer's type patients in Turkish population

Alzheimer’s disease (AD) is a chronic, neurodegenaration resulting in progressive cognitive decline leading to dementia. Mild cognitive impairment (MCI) is also a clinical definition of cognitive decline without functional impairment. Receptor for advanced glycation end products (RAGE) is one of the neuronal membrane receptors that binds amyloid beta peptide (Aβ) triggering Aβ-related pathologic signalling mechanisms. Soluble RAGE (sRAGE) is the soluble isoform of RAGE and it collects peripheral Aβ by acting as a sink, prevents both RAGE-AGE interaction and transfer of Aβ into brain.In this study, an association was investigated in Turkish cohorts of patients with dementia with Alzheimer's Type (DAT) and MCI patients by measuring serum sRAGE levels and by genotyping G82S polymorphism and comparing them to healthy control (HC) subjects.Although the serum sRAGE levels showed a decreasing manner among the groups, these differences were not statistically significant (p = 0.2). This is the first study for Turkish population.

Nitration of amyloid-β peptide (1–42) as a protective mechanism for the amyloid-β peptide (1–42) against copper ion toxicity

It is known that copper ion (Cu(II)) binds to amyloid-β peptide (Aβ), induces Aβ oligomer formation and ultimately exacerbates Aβ-aggregation neurotoxicity in Alzheimer's disease (AD). It becomes interesting to know that how this chemical modification of Aβ would affect interaction of Aβ and Cu(II) and their roles in the development of AD. In this work, we investigated the interaction of Aβ1–42 nitration with the toxic Cu(II). It showed that Cu(II)induced Aβ1–42 nitration in the presence of nitrite and hydrogen peroxide. Circular dichroism studies also revealed significant conformational change of Aβ1–42 and Tyr10 nitrated amyloid-β peptide(1–42) (Aβ1–42NT) when interacting with Cu(II). Even though nitration did not alter the binding of Aβ1–42 to Cu(II) or the peroxidative activity of Aβ1–42-Cu(II) complex, nitration ameliorated the aggregation and neurotoxicity of Aβ1–42 induced by Cu(II), which was also further confirmed by the cell study. Given our previous findings that Aβ nitration dramatically inhibited its aggregation and thus reduced its toxicity, we speculated that nitration of Aβ1–42 altered its intermolecular interaction, which protected itself against the toxicity of Cu(II). Based on this hypothesis, we propose that nitration of Aβ1–42 may be an important protective mechanism for normal function of Aβ1–42 and deserves more attention in AD drug development.

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

The cellular prion protein (PrPC) can act as a cell-surface receptor for β-amyloid (Aβ) peptide; however, a role for PrPC in the pathogenesis of Alzheimer's disease (AD) is contested. Here, we expressed a range of Aβ isoforms and PrPC in the Drosophila brain. We found that co-expression of Aβ and PrPC significantly reduces the lifespan, disrupts circadian rhythms, and increases Aβ deposition in the fly brain. In contrast, under the same conditions, expression of Aβ or PrPC individually did not lead to these phenotypic changes. In vitro studies revealed that substoichiometric amounts of PrPC trap Aβ as oligomeric assemblies and fragment-preformed Aβ fibers. The ability of membrane-anchored PrPC to trap Aβ as cytotoxic oligomers at the membrane surface and fragment inert Aβ fibers suggests a mechanism by which PrPC exacerbates Aβ deposition and pathogenic phenotypes in the fly, supporting a role for PrPC in AD. This study provides a second animal model linking PrPC expression with Aβ toxicity and supports a role for PrPC in AD pathogenesis. Blocking the interaction of Aβ and PrPC represents a potential therapeutic strategy.

Tocotrienol-Rich Fraction of Palm Oil Improves Behavioral Impairments and Regulates Metabolic Pathways in AβPP/PS1 Mice.

We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer’s disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction.

Effect of ferric citrate on amyloid-beta peptides behavior.

Amyloid beta (Aβ) aggregation and oxidative stress are two of the central events in Alzheimer's Disease (AD). Both these phenomena can be caused by the interaction of Aβ with metal ions. In the last years the interaction between ZnII , CuII , and Aβ was much studied, but between iron and Aβ it is still little known. In this work we determine how three Aβ peptides, present in AD, interact with FeIII -citrate. The three Aβ peptides are: full length Aβ1-42, an isoform truncated at Glutamic acid in position three, Aβ3-42, and its pyroglutamated form AβpE3-42. Conformation and morphology of the three peptides, aggregated with and without FeIII -citrate were studied. Besides, we have determined the strength of the interactions Aβ/FeIII -citrate studying the effect of ethylenediaminetetraacetic acid as chelator. Results reported here demonstrate that FeIII -citrate promotes the aggregation in all the three peptides. Moreover, Aspartic acid 1, Glutamic acid 3, and Tyrosine 10 have an important role in the coordination with iron, generating a more stable complex for Aβ1-42 compared to that for the truncated peptides.

Cysteine-Rich Repeat Domains 2 and 4 are Amyloid-β Binding Domains of Neurotrophin Receptor p75NTR and Potential Targets to Block Amyloid-β Neurotoxicity.

The p75 neurotrophin receptor (p75NTR) is an amyloid-β (Aβ) receptor that both mediates Aβ neurotoxicity and regulates Aβ production and deposition, thus playing an important role in the pathogenesis of Alzheimer's disease (AD). The extracellular domain of p75NTR (p75ECD), consisting of four cysteine-rich repeat domains (CRDs), was recently reported to be an endogenous anti-Aβ scavenger to block p75NTR-mediated neuronal death and neurite degeneration signaling of Aβ and pro-neurotrophins. Identification of the specific Aβ binding domains of p75NTR is crucial for illuminating their interactions and the etiology of AD. CRDs of p75ECD were obtained by expression of recombinant plasmids or direct synthesis. Aβ aggregation inhibiting test and immunoprecipitation assay were applied to locate the specific binding domains of Aβ to p75ECD. The Aβ neurotoxicity antagonistic effects of different CRDs were examined by cytotoxicity experiments including neurite outgrowth assay, propidium iodide (PI) staining, and MTT assay. In the Aβ aggregation inhibiting test, the fluorescence intensity in the CRD2 and CRD4 treatment groups was significantly lower than that in the CRD1 and CRD3 treatment groups. Immunoprecipitation assay and western blot confirmed that Aβ could bind to CRD2 and CRD4. Besides, CRD2 and CRD4 antagonized Aβ neurotoxicity suggested by longer neurite length, less PI labelled cells, and higher cell viability than the control group. Our results indicate that CRD2 and CRD4 are Aβ binding domains of p75NTR and capable of antagonizing Aβ neurotoxicity, and therefore are potential therapeutic targets to block the interaction of Aβ and p75NTR in the pathogenesis of AD.

The amyloid‐β peptide in Alzheimer's disease: molecular interactions and structure conversions

The amyloid β (Aβ) peptide consists of 39–43 residues and is the major component of the neuritic plaques in the brains of Alzheimer's disease (AD) patients. It is possible to study the peptide self‐aggregation process (“amyloid formation”, structures and kinetics) using biophysical methods such as NMR, fluorescence or CD spectroscopy. The interactions of Aβ(1–40) with small molecules, or metal ions such as Zn(II) or Cu(II), that modulate the aggregation process can be studied in semi‐stationary states by these methods. Kinetic effects on the amyloid formation process can be followed by fluorescence, after labeling the material rich in β‐structure by the amyloid‐specific dye Thioflavin T. The β‐hairpin structure of the peptide with a mainly unstructured N‐terminus appears to be a basic unit for formation of the larger amyloid structures associated with insoluble fibrils. Smaller oligomeric peptide aggregates, possibly the major cell toxic agents, can be studied by Soft Ionization Mass Spectrometry.Fluorescence Correlation Spectroscopy (FCS) shows the heterogeneity of the aggregation process of ThT‐labeled Aβ, in terms of time dependent amyloid aggregate sizes, on a single particle level. Modulation of the amyloid formation by Zn(II) or Cu(II) ions binding to specific residues in the N‐terminus of the Aβ peptide can be followed by the biophysical methods, showing changes in structures as well as kinetics for the aggregation process.Understanding the basic properties and reactions of the major participants in the chemical processes leading to AD gives a firm basis for the future development of agents that may be used in therapies against AD.Support or Funding InformationThe Swedish Research Council, The Alzheimer Foundation, The Magn. Bergvall FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Analysis of Physicochemical Interaction of Aβ40 with a GM1 Ganglioside-Containing Lipid Membrane.

The interaction of amyloid beta (Aβ) peptides with the cell membrane is one of the factors enhancing Aβ aggregation, which is closely related to neurodegenerative disease. In this work, we performed molecular dynamics (MD) simulation to investigate the initial stage of adhesion of Aβ40 to a GM1 ganglioside-containing membrane. Conformational change of Aβ40 due to interaction with the membrane was monitored and compared with that of Aβ42 observed in the previous study. Multiple computational trials were executed to analyze the probability of Aβ binding using a calculation model consisting of a GM1-containing mixed lipid membrane, a water layer, ions, and Aβ40. A single long-time MD simulation was also carried out. It was suggested from the simulation that a cluster of sialic acids of GM1 head groups often caught the side chain of His13 or His14 of Aβ40 in the early stage of the MD simulations. Afterward, the main chain of Leu34 formed many hydrogen bonds with gangliosides. These residues cooperatively work for Aβ40 to be held on the lipid membrane. It is notable that Aβ40 was observed to be deeply inserted into the head group region of the lipid membrane in some computational trials. In the insertion, Aβ40 occasionally formed a hydrogen bond with sphingomyelin. The difference in the secondary structure between Aβ40 and Aβ42 was an important factor for Aβ40 to be deeply inserted into the membrane.

Membrane Interaction and Assembly Mechanism of Aβ in Alzheimer's Disease

Membrane Interaction and Assembly Mechanism of Aβ in Alzheimer's Disease

Free Heme and Amyloid-β: A Fatal Liaison in Alzheimer's Disease.

While the etiology of Alzheimer's disease (AD) is still unknown, an increased formation of amyloid-β (Aβ) peptide and oxidative processes are major pathological mechanism of the disease. The interaction of Aβ with free heme leads to the formation of peroxidase-active Aβ-heme complexes. However, enzyme-kinetic data and systematic mutational studies are still missing. These aspects were addressed in this study to evaluate the role of Aβ-heme complexes in AD. The enzyme-kinetic measurements showed peroxidase-specific pH- and H2O2-dependencies. In addition, the enzymatic activity of Aβ-heme complexes constantly increased at higher peptide excess. Moreover, the role of the Aβ sequence for the named enzymatic activity was tested, depicting human-specific R5, Y10, and H13 as essential amino acids. Also by studying Y10 as an endogenous peroxidase substrate for Aβ-heme complexes, ratio-specific effects were observed, showing an optimal dityrosine formation at an about 40-fold peptide excess. As dityrosine formation promotes Aβ fibrillation while free heme disturbs protein aggregation, we also investigated the effect of Aβ-heme complex-derived peroxidase activity on the formation of Aβ fibrils. The fluorescence measurements showed a different fibrillation behavior at strong peroxidase activity, leading also to altered fibril morphologies. The latter was detected by electron microscopy. As illustrated by selected in vivo measurements on a mouse model of AD, the disease is also characterized by Aβ-derived microvessel destructions and hemolytic processes. Thus, thrombo-hemorrhagic events are discussed as a source for free heme in brain tissue. In summary, we suggest the formation and enzymatic activity of Aβ-heme complexes as pathological key features of AD.

Stereochemistry and amyloid inhibition: Asymmetric triplex metallohelices enantioselectively bind to Aβ peptide.

Stereochemistry is vital for pharmaceutical development and can determine drug efficacy. Herein, 10 pairs of asymmetric triplex metallohelix enantiomers as a library were used to screen inhibitors of amyloid β (Aβ) aggregation via a fluorescent cell-based high-throughput method. Intriguingly, Λ enantiomers show a stronger inhibition effect than Δ enantiomers. In addition, the metallohelices with aromatic substituents are more effective than those without, revealing that these groups play a key role in the Aβ interaction. Fluorescence stopped-flow kinetic studies indicate that binding of the Λ enantiomer to Aβ is much faster than that of the Δ enantiomer. Furthermore, studies in enzyme digestion, isothermal titration calorimetry, nuclear magnetic resonance, and computational docking demonstrate that the enantiomers bind to the central hydrophobic α-helical region of Aβ13-23, although with different modes for the Λ and Δ enantiomers. Finally, an in vivo study showed that these metallohelices extend the life span of the Caenorhabditis elegans CL2006 strain by attenuating Aβ-induced toxicity. Our work will shed light on the design and screening of a metal complex as an amyloid inhibitor against Alzheimer's disease.

Interaction of Aβ1-42 peptide or their variant with model membrane of different composition probed by infrared nanospectroscopy.

Toxicity of Aβ peptides involved in Alzheimer's disease is linked to the interaction of intermediate species with membranes. Nanoscale Infrared Spectroscopy enhances the study of the morphology and the secondary structure of the peptides as fibers or oligomers interacting with membranes of different compositions, with nanometer scale resolution. Membrane models are used to investigate the role of different lipids in their interactions with Aβ peptides. This work clearly brings to light that the presence of cholesterol in membranes is favorable to the interaction with Aβ peptides in oligomers or aggregates.

Impact of the Coagulation System on the Pathogenesis of Alzheimer's Disease

Alzheimer's disease (AD) leads to cognitive impairment and is eventually fatal. The cognitive decline is associated with extensive neuronal degeneration. The most well-known pathological features of AD are extracellular Aβ plaques, intracellular tau tangles, neuroinflammation, and neuronal loss. Less discussed is that AD is often associated with cerebrovascular abnormalities. The symptoms of AD and cerebrovascular pathology could be independent co-morbidities, with both being increased in aging populations. However, it is also possible that there is a mechanistic link between AD and vascular pathology. The interaction of Aβ with fibrin(ogen) can lead to increased fibrin deposition in cerebral blood vessels, and these accumulated fibrin deposits may disrupt cerebral blood flow and induce microinfarcts, inflammation, and BBB damage, all of which are aspects of cerebrovascular dysfunction observed in AD. At the same time, Ab's ability to activate FXII may contribute to increased fibrin generation through the intrinsic coagulation pathway as well as to increased inflammation and vascular permeability through bradykinin release from HK. These possible roles of Aβ in thrombosis, fibrinolysis, and inflammation via its interaction with fibrinogen and FXII, summarized in Figure 1, will be discussed. DisclosuresNo relevant conflicts of interest to declare.