Amyloid-β Species Research Articles

Development of Off-On Near-Infrared Fluorescent Probes for Sensitive In Vivo Imaging of Amyloid-β Species with Enhanced Pharmacokinetics.

The fluorescent imaging of pathologically accumulated β-amyloid (Aβ) proteins is of significant importance to the diagnosis of Alzheimer's disease (AD). In the paper, we prepare two new NIR probes, NIR-1 and NIR-2, through hydrophilic modification of introducing water-soluble bioactive groups such as polyethylene glycol (PEG) and morpholine to tune in vivo pharmacokinetics for specific detection of soluble and insoluble Aβ species. The in vitro assessments confirm that both NIR-1 and NIR-2 display strong near-infrared (NIR) fluorescence (FL) enhancement upon interaction with Aβ42 monomers, oligomers or aggregates (λem>670 nm) and show highly sensitive, rapid and selective response towards Aβ42 species. After i. v. injection, each probe showed fast blood-brain barrier (BBB) penetration and immediately produced intense FL signals in the brain of APP/PS1 AD model mice at 10 min. Moreover, compared with NIR-2, NIR-1 bearing a hydrophilic PEG chain displayed not only more rapid clearance but also lower background signal to efficiently distinguish APP/PS1 mice and wild-type mice with higher signal-to-background ratio, which was further validated by ex vivo histological staining of brain tissues. Therefore, due to its excellent pharmacokinetics, NIR-1 shows great promise as an effective NIR probe for specific detection of Aβ species.

Detecting and Tracking β-Amyloid Oligomeric Forms and Dynamics In Vitro by a High-Sensitivity Fluorescent-Based Assay.

Aggregation of β-amyloid protein is a hallmark pathology of the neurodegenerative disorder Alzheimer's disease and proceeds from monomers to insoluble misfolded fibril forms via soluble and highly toxic oligomeric intermediates. Given the dual feature of being the most toxic form of the Aβ aggregate proteome and an early marker of pathogenesis, there is a need for sensitive methods that can be used to detect Aβ oligomers and investigate the dynamics of aggregation. Herein, we describe a method based on the application of an oligomer-sensitive fluorescent chemical probe pTP-TFE combined with the use of a QIAD (Quantitative determination of Interference with Aβ Aggregate Size Distribution) assay to correctly identify Aβ oligomers in high sensitivity. pTP-TFE was evaluated and compared to thioflavin T and pFTAA, the two most widely used amyloid fibril dyes, and shown to be the only probe capable of detecting significant differences across all oligomeric species of β-amyloid. Furthermore, by observing changes in pTP-TFE fluorescence emission over time, we could track the dynamics of oligomer populations and thereby obtain kinetic information on the Aβ42 dynamic aggregation model. Therefore, we have established a highly sensitive, readily available, and simple method for studying β-amyloid protein aggregation dynamics.

Morphological and Molecular Profiling of Amyloid-β Species in Alzheimer's Pathogenesis.

Alzheimer's disease (AD) is the most common form of dementia around the world (~ 65%). Here, we portray the neuropathology of AD, biomarkers, and classification of amyloid plaques (diffuse, non-cored, dense core, compact). Tau pathology and its involvement with Aβ plaques and cell death are discussed. Amyloid cascade hypotheses, aggregation mechanisms, and molecular species formed in vitro and in vivo (on- and off-pathways) are described. Aβ42/Aβ40 monomers, dimers, trimers, Aβ-derived diffusible ligands, globulomers, dodecamers, amylospheroids, amorphous aggregates, protofibrils, fibrils, and plaques are characterized (structure, size, morphology, solubility, toxicity, mechanistic steps). An update on AD-approved drugs by regulatory agencies, along with new Aβ-based therapies, is presented. Beyond prescribing Aβ plaque disruptors, cholinergic agonists, or NMDA receptor antagonists, other therapeutic strategies (RNAi, glutaminyl cyclase inhibitors, monoclonal antibodies, secretase modulators, Aβ aggregation inhibitors, and anti-amyloid vaccines) are already under clinical trials. New drug discovery approaches based on "designed multiple ligands", "hybrid molecules", or "multitarget-directed ligands" are also being put forward and may contribute to tackling this highly debilitating and fatal form of human dementia.

Degradation of Amyloid-β Species by Multi-Copper Oxidases.

Reduction of the production of amyloid-β (Aβ) species has been intensively investigated as potential therapeutic approaches for Alzheimer's disease (AD). However, the degradation of Aβ species, another potential beneficial approach, has been far less explored. To investigate the potential of multi-copper oxidases (MCOs) in degrading Aβ peptides and their potential benefits for AD treatment. We investigated the degradation efficiency of MCOs by using electrophoresis and validated the ceruloplasmin (CP)-Aβ interaction using total internal reflection fluorescence microscopy, fluorescence photometer, and fluorescence polarization measurement. We also investigated the therapeutic effect of ascorbate oxidase (AO) by using induced pluripotent stem (iPS) neuron cells and electrophysiological analysis with brain slices. We discovered that CP, an important MCO in human blood, could degrade Aβ peptides. We also found that other MCOs could induce Aβ degradation as well. Remarkably, we revealed that AO had the strongest degrading effect among the tested MCOs. Using iPS neuron cells, we observed that AO could rescue neuron toxicity which induced by Aβ oligomers. In addition, our electrophysiological analysis with brain slices suggested that AO could prevent an Aβ-induced deficit in synaptic transmission in the hippocampus. To the best of our knowledge, our report is the first to demonstrate that MCOs have a degrading function for peptides/proteins. Further investigations are warranted to explore the possible benefits of MCOs for future AD treatment.

Tailoring near-infrared amyloid-β probes with high-affinity and low background based on CN and amphipathic regulatory strategies and in vivo imaging of AD mice

Amyloid-β (Aβ) species (Aβ fibrils and Aβ plaques), as one of the typical pathological markers of Alzheimer's disease (AD), plays a crucial role in AD diagnosis. Currently, some near-infrared I (NIR I) Aβ probes have been reported in AD diagnosis. However, they still face challenges such as strong background interference and the lack of effective probe design. In this study, we propose molecular design strategy that incorporates CN group and amphiphilic modulation to synthesize a series of amphiphilic NIR I Aβ probes, surpassing the commercial probe ThT and ThS. Theoretical calculations indicate that these probes exhibit stronger interaction with amino acid residues in the cavities of Aβ. Notably, the probes containing CN group display the ability of binding two distinct sites of Aβ, which dramatically enhanced the affinity to Aβ species. Furthermore, these probes exhibit minimal fluorescence in aqueous solution and offer ultra-high signal-to-noise ratio (SNR) for in vitro labeling, even in wash-free samples. Finally, the optimal probe DM-V2CN-PYC3 was utilized for in vivo imaging of AD mice, demonstrating its rapid penetration through the blood-brain barrier and labelling to Aβ species. Moreover, it enabled long-term monitoring for a duration of 120 min. These results highlight the enhanced affinity and superior performance of the designed NIR I Aβ probe for AD diagnosis. The molecular design strategy of CN and amphiphilic modulation presents a promising avenue for the development Aβ probes with low background in vivo/in vitro imaging for Aβ species.

β-Amyloid species production and tau phosphorylation in iPSC-neurons with reference to neuropathologically characterized matched donor brains.

A basic assumption underlying induced pluripotent stem cell (iPSC) models of neurodegeneration is that disease-relevant pathologies present in brain tissue are also represented in donor-matched cells differentiated from iPSCs. However, few studies have tested this hypothesis in matched iPSCs and neuropathologically characterized donated brain tissues. To address this, we assessed iPSC-neuron production of β-amyloid (Aβ) Aβ40, Aβ42, and Aβ43 in 24 iPSC lines matched to donor brains with primary neuropathologic diagnoses of sporadic AD (sAD), familial AD (fAD), control, and other neurodegenerative disorders. Our results demonstrate a positive correlation between Aβ43 production by fAD iPSC-neurons and Aβ43 accumulation in matched brain tissues but do not reveal a substantial correlation in soluble Aβ species between control or sAD iPSC-neurons and matched brains. However, we found that the ApoE4 genotype is associated with increased Aβ production by AD iPSC-neurons. Pathologic tau phosphorylation was found to be increased in AD and fAD iPSC-neurons compared to controls and positively correlated with the relative abundance of longer-length Aβ species produced by these cells. Taken together, our results demonstrate that sAD-predisposing genetic factors influence iPSC-neuron phenotypes and that these cells are capturing disease-relevant and patient-specific components of the amyloid cascade.

Thiophene-Based Ligands for Specific Assignment of Distinct Aβ Pathologies in Alzheimer's Disease.

Aggregated species of amyloid-β (Aβ) are one of the pathological hallmarks in Alzheimer's disease (AD), and ligands that selectively target different Aβ deposits are of great interest. In this study, fluorescent thiophene-based ligands have been used to illustrate the features of different types of Aβ deposits found in AD brain tissue. A dual-staining protocol based on two ligands, HS-276 and LL-1, with different photophysical and binding properties, was developed and applied on brain tissue sections from patients affected by sporadic AD or familial AD associated with the PSEN1 A431E mutation. When binding to Aβ deposits, the ligands could easily be distinguished for their different fluorescence, and distinct staining patterns were revealed for these two types of AD. In sporadic AD, HS-276 consistently labeled all immunopositive Aβ plaques, whereas LL-1 mainly stained cored and neuritic Aβ deposits. In the PSEN1 A431E cases, each ligand was binding to specific types of Aβ plaques. The ligand-labeled Aβ deposits were localized in distinct cortical layers, and a laminar staining pattern could be seen. Biochemical characterization of the Aβ aggregates in the individual layers also showed that the variation of ligand binding properties was associated with certain Aβ peptide signatures. For the PSEN1 A431E cases, it was concluded that LL-1 was binding to cotton wool plaques, whereas HS-276 mainly stained diffuse Aβ deposits. Overall, our findings showed that a combination of ligands was essential to identify distinct aggregated Aβ species associated with different forms of AD.

A Near-infrared Fluorescence and Positron Emission Tomography Bimodal Probe for In Vivo Imaging of Amyloid-β Species.

Noninvasive imaging of amyloid-β (Aβ) species in vivo is important for the early diagnosis of Alzheimer's disease (AD). In this paper, we report a near-infrared (NIR) fluorescence (FL) and positron emission tomography (PET) bimodal probe (NIR-[68Ga]) for in vivo imaging of both soluble and insoluble Aβ species. NIR-[68Ga] holds a high binding affinity, high selectivity and high sensitivity toward Aβ42 monomers, oligomers, and aggregates in vitro. In vivo imaging results show that NIR-[68Ga] can cross the blood-brain-barrier (BBB), and produce significantly higher PET and NIR FL bimodal signals in the brains of APP/PS1 transgenic AD mice relative to that of age-matched wild-type mice, which are also validated by the ex vivo autoradiography and histological staining images. Our results demonstrate that NIR-[68Ga] is an efficient NIR FL and PET bimodal probe for the sensitive imaging of soluble and insoluble Aβ species in AD mice.

Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways

Alzheimer’s Disease (AD) is a disorder characterized by cognitive decline, neurodegeneration, and accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. Dysregulation of epigenetic histone modifications may lead to expression of transcriptional programs that play a role either in protecting against disease genesis or in worsening of disease pathology. One such histone modification, acetylation of histone H3 lysine residue 27 (H3K27ac), is primarily localized to genomic enhancer regions and promotes active gene transcription. We previously discovered H3K27ac to be more abundant in AD patient brain tissue compared to the brains of age-matched non-demented controls. In this study, we use iPSC-neurons derived from familial AD patients with an amyloid precursor protein (APP) duplication (APPDup neurons) as a model to study the functional effect of lowering CBP/P300 enzymes that catalyze H3K27ac. We found that homeostatic amyloid-reducing genes were upregulated in the APPDup neurons compared to non-demented controls. We lowered CBP/P300 to reduce H3K27ac, which led to decreased expression of numerous of these homeostatic amyloid-reducing genes, along with increased extracellular secretion of a toxic amyloid-β species, Aβ(1–42). Our findings suggest that epigenomic histone acetylation, including H3K27ac, drives expression of compensatory genetic programs in response to AD-associated insults, specifically those resulting from APP duplication, and thus may play a role in mitigating AD pathology in neurons.

Purinergic Receptor P2Y12-Mediated Tau Internalization in Microglia.

Microglia are the resident brain macrophage cells that are involved in constant surveillance of brain microenvironment. In Alzheimer's disease, microglia get over activated upon the accumulation of Tau and amyloid-β species in the extracellular space, ultimately leading to neurodegeneration. Microglia phagocytose the extracellular Tau species by several mechanisms among which P2Y12 receptor-mediated internalization of extracellular Tau is recently studied. Extracellular Tau activates microglia and directly interacts with the P2Y12 receptor. Tau-receptor complex is then internalized followed by perinuclear accumulation and lysosomal degradation. Upon microglial activation by extracellular Tau, P2Y12 receptor is also involved in membrane-associated actin remodeling which has its key role in active migration and phagocytosis.

The C-terminal domain of the antiamyloid chaperone DNAJB6 binds to amyloid-β peptide fibrils and inhibits secondary nucleation

The DNAJB6 chaperone inhibits fibril formation of aggregation-prone client peptides through interaction with aggregated and oligomeric forms of the amyloid peptides. Here, we studied the role of its C-terminal domain (CTD) using constructs comprising either the entire CTD or the first two or all four of the CTD β-strands grafted onto a scaffold protein. Each construct was expressed as WT and as a variant with alanines replacing five highly conserved and functionally important serine and threonine residues in the first β-strand. We investigated the stability, oligomerization, antiamyloid activity, and affinity for amyloid-β (Aβ42) species using optical spectroscopy, native mass spectrometry, chemical crosslinking, and surface plasmon resonance technology. While DNAJB6 forms large and polydisperse oligomers, CTD was found to form only monomers, dimers, and tetramers of low affinity. Kinetic analyses showed a shift in inhibition mechanism. Whereas full-length DNAJB6 activity is dependent on the serine and threonine residues and efficiently inhibits primary and secondary nucleation, all CTD constructs inhibit secondary nucleation only, independently of the serine and threonine residues, although their dimerization and thermal stabilities are reduced by alanine substitution. While the full-length DNAJB6 inhibition of primary nucleation is related to its propensity to form coaggregates with Aβ, the CTD constructs instead bind to Aβ42 fibrils, which affects the nucleation events at the fibril surface. The retardation of secondary nucleation by DNAJB6 can thus be ascribed to the first two β-strands of its CTD, whereas the inhibition of primary nucleation is dependent on the entire protein or regions outside the CTD.

Development of 11 C-labeled CRANAD-102 for positron emission tomography imaging of soluble Aβ-species.

CRANAD-102, a selective near-infrared fluorescent tracer targeting soluble amyloid-β (Aβ) species, has recently attracted attention due to its potential to be used as a diagnostic tool for early stages of Alzheimer's disease (AD). Development of a positron emission tomography (PET) tracer based on CRANAD-102 could as such allow to noninvasively study soluble and protofibrillar species of Aβ in humans. These soluble and protofibrillar species are thought to be responsible to cause AD. Within this work, we successfully 11 C-labeled CRANAD-102 via a Suzuki-Miyaura reaction in a RCС of 48 ±9%, with a RCP of >96% and a molar activity (Am ) of 25 ±7GBq/μmol. Future studies have to be conducted to evaluate if [11 C]CRANAD-102 can be used to detect soluble protofibrils in vivo and if [11 C]CRANAD-102 can be used to detect AD earlier as possible with current diagnostics.

Target-modulated mineralization of wood channels as enzyme-free electrochemical sensors for detecting amyloid-β species

Alzheimer's disease (AD) is an irreversible brain disorder, which has been found to be associated with neurotoxic amyloid-β oligomers (AβO). The early diagnosis of AD is still a great challenge. Herein, inspired by the hierarchical channel structure of natural wood, we design and demonstrate a low-cost and sensitive wood channel-based fluidic membrane for electrochemical sensing of AβO1-42. In this design, Zn/Cu-2-methylimidazole (Zn/Cu-Hmim) with artificial peroxidase (POD)-like activity was asymmetrically fabricated at one side of the wood channels by biomimetic mineralization and a subsequent ion exchange reaction. The strong affinity between Cu(II) and AβO1-42 enables Cu(II) species in Zn/Cu-Hmim to be extracted by AβO1-42, thus suppressing the POD-like performance via Zn/Cu-Hmim disassembly. Using Zn/Cu-Hmim to catalyze the oxidation reaction of 2,2′-diazo-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) by H2O2, the current–voltage (I–V) properties of wood channels are influenced by the generated oxidation product (ABTS•+), thus providing information useful for the quantitative analysis of AβO1-42. Importantly, the three aggregation states of Aβ1-42 (AβM1-42, AβO1-42, and AβF1-42) can also be identified, owing to the affinity difference and available reaction sites. The proposed wood membrane provides a novel, assessable, and scalable channel device to develop sensitive electrochemical sensors; moreover, the sustainable wood materials represent alternative candidates for developing channel-structured sensing platforms.

Recent Advances in the Development of Near-Infrared Fluorescent Probes for the in Vivo Brain Imaging of Amyloid-β Species in Alzheimer's Disease.

The deposition of β-amyloid (Aβ) plaques in the parenchymal and cortical regions of the brain of Alzheimer's disease (AD) patients is considered the foremost pathological hallmark of the disease. The early diagnosis of AD is paramount in order to effective management and treatment of the disease. Developing near-infrared fluorescence (NIRF) probes targeting Aβ species is a potential and attractive approach suitable for the early and timely diagnosis of AD. The advantages of the NIRF probes over other tools include real-time detection, higher sensitivity, resolution, comparatively inexpensive experimental setup, and noninvasive nature. Currently, enormous progress is being observed in the development of NIRF probes for the in vivo imaging of Aβ species. Several strategies, i.e., the classical push-pull approach, "turn-on" effect, aggregation-induced emission (AIE), and resonance energy transfer (RET), have been exploited for development. We have outlined and discussed the recently emerged NIRF probes with different design strategies targeting Aβ species for ex vivo and in vivo imaging. We believe that understanding the recent development enables the prospect of the rational design of probes and will pave the way for developing future novel probes for early diagnosis of AD.

Effect of Cross-Seeding of Wild-Type Amyloid-β1-40 Peptides with Post-translationally Modified Fibrils on Internal Dynamics of the Fibrils Using Deuterium Solid-State NMR.

Post-translationally modified (PTM) amyloid-β (Aβ) species can play an important role in modulating Alzheimer's disease pathology. These relatively less populated modifications can cross-seed the wild-type Aβ peptides to produce fibrils that retain many structural and functional features of the original PTM variants. We focus on studies of internal flexibility in the cross-seeded Aβ1-40 fibrils originating from seeding with two PTM variants with modifications in the disordered N-terminal domain: ΔE3 truncation and S8-phosphorylation. We employ an array of 2H solid-state NMR techniques, including line shape analysis over a broad temperature range, longitudinal relaxation, and quadrupolar CPMG, to assess the dynamics of the cross-seeded fibrils. The focus is placed on selected side-chain sites in the disordered N-terminal domain (G9 and V12) and hydrophobic core methyl and aromatic groups (L17, L34, M35, V36, and F19). We find that many of the essential features of the dynamics present in the original PTM seeds persist in the cross-seeded fibrils, and several of the characteristic features are even enhanced. This is particularly true for the activation energies of the rotameric motions and large-scale rearrangements of the N-terminal domain. Thus, our results on the dynamics complement prior structural and cell toxicity studies, suggesting that many PTM Aβ species can aggressively cross-seed the wild-type peptide in a manner that propagates the PTM's signature.

P-100 - In vivo evaluation of carbon-11 labeled CRANAD-102 as a potential PET tracer for soluble species of amyloid-β species in the brain

P-100 - In vivo evaluation of carbon-11 labeled CRANAD-102 as a potential PET tracer for soluble species of amyloid-β species in the brain

Strategic Design of Amyloid-β Species Fluorescent Probes for Alzheimer's Disease.

Alzheimer's disease (AD) is a high mortality and high disability rates neurodegenerative disease characterized by irreversible progression and poses a significant social and economic burden throughout the world. However, currently approved AD therapeutic agents only alleviate symptoms and there is still a lack of practical therapeutic regimens to stop or slow the progression of this disease. Thus, there is urgently needed novel diagnosis tools and drugs for early diagnosis and treatment of AD. Among several AD pathological hallmarks, amyloid-β (Aβ) peptide deposition is considered a critical initiating factor in AD. In recent years, with the advantages of excellent sensitivity and high resolution, near-infrared fluorescence (NIRF) imaging has attracted the attention of many researchers to develop Aβ plaque probes. This review mainly focused on different NIRF probe design strategies for imaging Aβ species to pave the way for the future design of novel NIRF probes for early diagnosis AD.

Dual-Emission GFP Chromophore-Based Derivative for Imaging and Discriminating Aβ Oligomers and Aggregates

β-Amyloid deposition is one of the main pathological features of Alzheimer's disease (AD). The development of fluorescent probes targeting specific β-amyloid species has recently become an attractive strategy to achieve the early diagnosis of AD. In this work, a dual-channel fluorescent protein chromophore derivative C17 was rationally designed and synthesized for the detection and discrimination of Aβ42 aggregates and oligomers. C17 exhibits a specific turn-on emission peak for Aβ42 oligomers at ∼470 nm (peak A) and a peak at ∼600 nm (peak B) for both Aβ42 oligomers and Aβ42 aggregates. Taking advantage of the dual emission of the probe, the dynamic aggregation process of the Aβ42 peptide was monitored in solution. Moreover, double staining of brain sections from transgenic AD mice revealed that peak A of C17 preferentially detected Aβ42 oligomers, whereas peak B was more sensitive to Aβ42 aggregates. The fact that probe C17 can be used for dissecting these two Aβ42 species makes C17 a comprehensive tool for β-amyloid aggregation studies in AD research.

Engineering of donor-acceptor-donor curcumin analogues as near-infrared fluorescent probes for in vivo imaging of amyloid-β species

Near-infrared (NIR) fluorescent imaging of both soluble and insoluble Aβ species in the brain of Alzheimer's disease (AD) is crucial for the early diagnosis and intervention of AD. To date, a variety of NIR fluorescent probes have been reported for the detection of Aβ species. Among these probes, CRANAD-58 was reported to have the capability to detect both soluble and insoluble Aβ species, which is vital to monitor the changes of Aβ species during the pathological course of the disease. Though CRANAD-58 has shown promise to noninvasively detect Aβ species in transgenic AD mice, the emission wavelength (~670 nm) is still too short for further applications. Therefore, new probes with longer emission wavelength and improved physiological properties are in highly demand. Herein, we report the design and engineering of nine donor-acceptor-donor molecules as “off-on” near-infrared fluorescent probes for in vivo imaging of both soluble and insoluble Aβ species in living AD mice owing to its improved in vitro properties and in vivo performance.Methods: We report a two-round strategy to develop nine “off-on” NIR fluorescence probes via structural modification of a curcumin analogue-based donor-acceptor-donor architecture. In round one, probes 1 and 2 were synthesized, and probe 2 was identified to be an optimum probe as it showed distinct “off-on” NIR fluorescence at > 690 nm upon binding to Aβ monomers, oligomers and aggregates. To further improve the in vivo performance, further structural modification of probe 2 into probes 3-9 was then conducted. The fluorescence response with Aβ species and histological staining in vitro and in vivo imaging of Aβ species in APP/PS1 transgenic AD mice and age-matched wild-type mice were performed.Results: We demonstrate that, compared to probe 2, probe 9 with improved physiological properties hold the fastest kinetics (~10 min) to produce not only higher brain fluorescence intensity in 10-month-old APP/PS1 transgenic AD mice, but also afford a higher discrepancy in brain fluorescence to discriminate AD mice from wild-type (WT) mice. Probe 9 also hold the ability to detect soluble Aβ species in 6-month-old APP/PS1 transgenic mice. Probe 9 was further applied for dynamic visualization of Aβ plaques in a skull-thinning 14-month-old APP/PS1 mouse, which revealed its immediate penetration into brain parenchyma and selective labeling of both parenchymal and angiopathic Aβ plaques. In addition, probe 9 possessed significantly high attenuation effect on the aggregation of Aβ monomers.Conclusion: Our results demonstrate the good potential of probe 9 for longitudinal NIR fluorescence imaging of soluble and insoluble Aβ species in APP/PS1 transgenic AD mice, which may act as a useful tool for early diagnosis and intervention of AD.

Fas Apoptosis Inhibitory Molecule Blocks and Dissolves Pathological Amyloid-β Species.

A number of neurodegenerative diseases are associated with the accumulation of misfolded proteins, including Alzheimer’s disease (AD). In AD, misfolded proteins such as tau and amyloid-β (Aβ) form pathological insoluble deposits. It is hypothesized that molecules capable of dissolving such protein aggregates might reverse disease progression and improve the lives of afflicted AD patients. Here we report new functions of the highly conserved mammalian protein, Fas Apoptosis Inhibitory Molecule (FAIM). We found that FAIM-deficient Neuro 2A cells accumulate Aβ oligomers/fibrils. We further found that recombinant human FAIM prevents the generation of pathologic Aβ oligomers and fibrils in a cell-free system, suggesting that FAIM functions without any additional cellular components. More importantly, recombinant human FAIM disaggregates and solubilizes established Aβ fibrils. Our results identify a previously unknown, completely novel candidate for understanding and treating irremediable, irreversible, and unrelenting neurodegenerative diseases.