Insoluble Plaques Research Articles

Beta-Amyloid Monoclonal Antibodies for Alzheimer's Disease: Development and Challenges

As one of the most common diseases of the elderly, the detection and diagnosis of Alzheimer's disease (AD) remain a challenge at the early stage. As the disease progresses, patients will suffer from memory and cognitive loss, which will impair their ability to live independently. The care required for these patients will be costly and time-consuming, placing a significant burden on both the family and society. At the same time, Alzheimer's disease has a complex pathogenesis and there is still and there is an unmet need for drugs that can reverse the disease. The beta-amyloid (Aβ) proteins produced by improper cleavage of amyloid precursor proteins tend to aggregate into insoluble plaques in the brain. This study reviews the latest progress in the treatment of AD with Aβ monoclonal antibodies (mAbs). In recent years, aducanumab, lecanemab, donenamab have been successively approved. Besides, small molecule drugs also play an important role in AD treatment. Despite the inability to impede the progression of the disease, they are still irreplaceable and effective in relieving symptoms at this stage. In addition, as Aβ deposition begins decades before clinical symptoms appear, advances in diagnostic technology are essential for early intervention. Future research needs to pay more attention to the side effects of this therapy and their solutions.

Polyphenols and Their Biogenic Nano-Formulations Targeting BACE1 as Anti-Amyloid Therapies; Meeting the Challenges of Bioavailability, Safety, and Specificity for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), a progressiveneurodegenerative condition is marked by extensive damage in the brain and dementia. Among the pathological hallmarks of AD is beta-amyloid (Aβ). Production of toxic Aβ oligomers production and accumulation in the brain is among the characteristic features of the disease. The abnormal accumulation Aβ is initiated by the catalytic degradation of Amyloid Precursor Proteins (APP) by Beta Amyloid Cleaving Enzyme 1 (BACE1) to generate insoluble amyloid plaques. The abnormal proteins are mitochondrial poison which disrupt the energy production and liberate excessive free radicals causing neuronal damage and mutations. Consequently, targeting Aβ-associated pathways has become a focus in the pursuit of developing effective AD treatments. An obstacle faced by many medications used to treat neurodegenerative diseases (NDs) is the restricted permeability across the blood-brain barrier (BBB). Unfortunately, no anti-amyloid drug is clinically approved till now. Recent advancements in nanotechnology have provided a possible solution for delivering medications to specific targets. By integrating natural products with nano-medicinal approaches, it is possible to develop novel and highly efficient therapeutic strategies for the treatment of AD.

Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer’s disease

BackgroundThe accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer’s disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored.MethodsWe generated an oligodendrocyte-specific Bace1 knockout model (Bace1fl/fl;Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1fl/fl;Olig2-Cre model with heterozygous AppNL−G−F/wt knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background.ResultsBace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1fl/fl;Olig2-Cre and age-matched Bace1fl/fl control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1fl/fl;AppNL−G−F/wt). Insoluble Aβ1–40 and Aβ1–42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APPNL−G−F/wt knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1.ConclusionOur results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies.

Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer's Disease Using Quantitative Systems Pharmacology Model.

ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD. The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22]. Subjects with positive CSF biomarkers for amyloid (Aβ42/Aβ40) and tau pathology (p-tau181) were enrolled, with serial CSF and plasma levels of Aβ42 and Aβ40 measured over 104 weeks. Longitudinal changes of CSF Aβ42, plasma Aβ42/Aβ40 ratio, and cognitive Rey Auditory Verbal Learning Test (RAVLT) were compared with the established natural disease trajectories in AD using a QSP approach. The natural disease trajectory data for amyloid biomarkers and RAVLT were extracted from a QSP model and an Alzheimer's disease neuroimaging initiative population model, respectively. Analyses were stratified by disease severity and sex. A total of 84 subjects were enrolled. Excluding one subject who withdrew at the early stage of the trial, data from 83 subjects were used for this analysis. The ALZ-801 treatment arrested the progressive decline in CSF Aβ42 level and plasma Aβ42/Aβ40 ratio, and stabilized RAVLT over 104 weeks. Both sexes showed comparable responses to ALZ-801, whereas mild cognitive impairment (MCI) subjects (MMSE ≥ 27) exhibited a larger biomarker response compared with more advanced mild AD subjects (MMSE 22-26). In this genetically defined and biomarker-enriched early AD population, the QSP analysis demonstrated a positive therapeutic effect of oral ALZ-801 265 mg BID by arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent their aggregation into soluble neurotoxic oligomers and subsequently into insoluble fibrils and plaques over 104 weeks. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory decline of the RAVLT memory test, suggesting that the clinical benefits are consistent with its mechanism of action. This sequential effect arresting the disease progression on biomarkers and cognitive decline was more pronounced in the earlier symptomatic stages of AD. The QSP analysis provides fluid biomarker and clinical evidence for ALZ-801 as a first-in-class, oral small-molecule anti-Aβ oligomer agent with disease modification potential in AD. https://clinicaltrials.gov/study/NCT04693520.

Disease modifying effects of the amyloid-beta protofibril-selective antibody mAb158 in aged Tg2576 transgenic mice

Amyloid beta (Aβ) peptides, which aggregate to form neocortical plaques in Alzheimer's disease, exist in states that range from soluble monomers and oligomers/protofibrils to insoluble fibrillar amyloid. The present study evaluated the effects of mAb158, a mouse monoclonal antibody version of lecanemab that preferentially binds to soluble Aβ protofibrils, in aged transgenic mice (Tg2576) with Aβ pathology. Female Tg2576 mice (12 months old) received weekly intraperitoneal mAb158 (35 mg/kg) or vehicle for 4 weeks or for 18 weeks, with or without a subsequent 12-week off-treatment period. Aβ protofibril levels were significantly lower in mAb158-treated animals at both 4 and 18 weeks, while longer treatment duration (18 weeks) was required to observe significantly lower Aβ42 levels in insoluble brain fractions and lower Aβ plaque load. Following the off-treatment period, comparison of the vehicle- and mAb158-treated mice demonstrated that the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load remained significantly lower in mAb158-treated animals, as compared with age-matched controls. However, there was a significant increase of brain accumulation of both the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load after treatment cessation. Thus, repeated mAb158 treatment of aged Tg2576 mice first reduced Aβ protofibril levels within 4 weeks of treatment, which then was followed by a reduction of amyloid plaque pathology within 18 weeks of treatment. These effects were maintained 12 weeks after the final dose, indicating that mAb158 had a disease-modifying effect on the Aβ pathology in this mouse model. In addition, brain accumulation of both Aβ protofibril levels and amyloid pathology progressed after discontinuation of the treatment which supports the importance of continued treatment with mAb158 to maintain the effects on Aβ pathology.

In silico analysis of the use of solanine derivatives as a treatment for Alzheimer's disease

Alzheimer's disease (AD) is a brain illness that causes cognitive impairment in the elderly, especially females, as a result of genetics, hormones, and life experiences. It becomes more severe with age and is associated with cardiovascular disease, hypertension, and diabetes. Beta-amyloid plaques and hyper phosphorylated Tau protein buildup are common clinical findings. Misfiling of amyloid precursor protein (APP) and Amyloid beta peptide (Aβ) proteins contributes to Alzheimer's disease. Enzyme Acetylcholinesterase enzyme interacts with amyloid-beta, enhancing its accumulation in insoluble plaques, leading to successful treatment for Alzheimer's disease primarily based on lowering this enzyme. Treatments include using the Rivastigmine for mild, moderate, or severe Alzheimer's disease, which inhibits acetylcholinesterase, but may cause side effects; Solanine derivatives, nightshade toxin, it is cholinesterase inhibitory, may mitigate Alzheimer's illness is progressing. In this research utilized a molecular docking program, which is a computer's computational ability to determine the optimal position for a specific compound to bind to a protein or target, forming a target-ligand complex and displaying biological activity and aiding in the development of effective anti-AD treatments and understanding AD pathological mechanisms. The study examined complexes of 3LII (Acetylcholinesterase receptor) in the A and B chain with Solanine and Rivastigmine derivatives, using an in-silico approach. PyRx default sorter was used to improve docking accuracy. Four compounds were selected based on their higher binding affinities in chain A and B. The results showed that Solanine derivatives (alpha-Solanine, Beta1-Solanine and Beta2-Solanine) have higher binding strength (−9.0,-9.3 and −8.6) than Rivastigmine (−7.2) in chain A, and also the binding strength was high for the Solanine derivatives (alpha-Solanine, Beta1-Solanine, and Beta2-Solanine) (−9.0,-8.8 and −8.9) is higher than Rivastigmine (−6.0) in the chain B. Solanine derivatives showed higher binding strength with acetylcholinesterase, potentially for to reduce the progression of the disease.

A Copper-Selective Sensor and Its Inhibition of Copper-Amyloid Beta Aggregation

Copper is an essential trace metal for biological processes in humans and animals. A low level of copper detection at physiological pH using fluorescent probes is very important for in vitro applications, such as the detection of copper in water or urine, and in vivo applications, such as tracking the dynamic copper concentrations inside cells. Copper homeostasis is disrupted in neurological diseases like Alzheimer’s disease, and copper forms aggregates with amyloid beta (Ab42) peptide, resulting in senile plaques in Alzheimer’s brains. Therefore, a selective copper detector probe that can detect amyloid beta peptide-copper aggregates and decrease the aggregate size has potential uses in medicine. We have developed a series of Cu2+-selective low fluorescent to high fluorescent tri and tetradentate dentate ligands and conjugated them with a peptide ligand to amyloid-beta binding peptide to increase the solubility of the compounds and make the resultant compounds bind to Cu2+–amyloid aggregates. The copper selective compounds were developed using chemical scaffolds known to have high affinity and selectivity for Cu2+, and their conjugates with peptides were tested for affinity and selectivity towards Cu2+. The test results were used to inform further improvement of the next compound. The final Cu2+ chelator–peptide conjugate we developed showed high selectivity for Cu2+ and high fluorescence properties. The compound bound 1:1 to Cu2+ ion, as determined from its Job’s plot. Fluorescence of the ligand could be detected at nanomolar concentrations. The effect of this ligand on controlling Cu2+–Ab42 aggregation was studied using fluorescence assays and microscopy. It was found that the Cu2+–chelator–peptide conjugate efficiently reduced aggregate size and, therefore, acted as an inhibitor of Ab42-Cu2+ aggregation. Since high micromolar concentrations of Cu2+ are present in senile plaques, and Cu2+ accelerates the formation of toxic soluble aggregates of Ab42, which are precursors of insoluble plaques, the developed hybrid molecule can potentially serve as a therapeutic for Alzheimer’s disease.

Post-translational modifications of beta-amyloid alter its transport in the blood-brain barrier in vitro model.

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its post-translationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the blood-brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ42 containing isomerized Asp7 residue (iso-Aβ42) and Aβ42 containing phosphorylated Ser8 residue (pS8-Aβ42) crossed the BBB better than unmodified Aβ42, which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ42 an order of magnitude weaker than to Aβ42. Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment.

The Single Toxin Origin of Alzheimer's Disease and Other Neurodegenerative Disorders Enables Targeted Approach to Treatment and Prevention.

New data suggest that the aggregation of misfolded native proteins initiates and drives the pathogenic cascade that leads to Alzheimer's disease (AD) and other age-related neurodegenerative disorders. We propose a unifying single toxin theory of brain neurodegeneration that identifies new targets and approaches to the development of disease-modifying treatments. An extensive body of genetic evidence suggests soluble aggregates of beta-amyloid (Aβ) as the primary neurotoxin in the pathogenesis of AD. New insights from fluid biomarkers, imaging, and clinical studies provide further evidence for the decisive impact of toxic Aβ species in the initiation and progression of AD. Understanding the distinct roles of soluble and insoluble amyloid aggregates on AD pathogenesis has been the key missing piece of the Alzheimer's puzzle. Data from clinical trials with anti-amyloid agents and recent advances in the diagnosis of AD demonstrate that the driving insult in biologically defined AD is the neurotoxicity of soluble Aβ aggregates, called oligomers and protofibrils, rather than the relatively inert insoluble mature fibrils and amyloid plaques. Amyloid oligomers appear to be the primary factor causing the synaptic impairment, neuronal stress, spreading of tau pathology, and eventual cell death that lead to the clinical syndrome of AD dementia. All other biochemical effects and neurodegenerative changes in the brain that are observed in AD are a response to or a downstream effect of this initial toxic insult by oligomers. Other neurodegenerative disorders follow a similar pattern of pathogenesis, in which normal brain proteins with important biological functions become trapped in the aging brain due to impaired clearance and then misfold and aggregate into neurotoxic species that exhibit prion-like behavior. These aggregates then spread through the brain and cause disease-specific neurodegeneration. Targeting the inhibition of this initial step in neurodegeneration by blocking the misfolding and aggregation of healthy proteins has the potential to slow or arrest disease progression, and if treatment is administered early in the course of AD and other neurodegenerative disorders, it may delay or prevent the onset of clinical symptoms.

Contextualizing the Role of Osteopontin in the Inflammatory Responses of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by progressive accumulations of extracellular amyloid-beta (Aβ) aggregates from soluble oligomers to insoluble plaques and hyperphosphorylated intraneuronal tau, also from soluble oligomers to insoluble neurofibrillary tangles (NFTs). Tau and Aβ complexes spread from the entorhinal cortex of the brain to interconnected regions, where they bind pattern recognition receptors on microglia and astroglia to trigger inflammation and neurotoxicity that ultimately lead to neurodegeneration and clinical AD. Systemic inflammation is initiated by Aβ's egress into the circulation, which may be secondary to microglial activation and can confer both destructive and reparative actions. Microglial activation pathways and downstream drivers of Aβ/NFT neurotoxicity, including inflammatory regulators, are primary targets for AD therapy. Osteopontin (OPN), an inflammatory cytokine and biomarker of AD, is implicated in Aβ clearance and toxicity, microglial activation, and inflammation, and is considered to be a potential therapeutic target. Here, using the most relevant works from the literature, we review and contextualize the evidence for a central role of OPN and associated inflammation in AD.

Pathophysiological Aspects and Therapeutic Armamentarium of Alzheimer's Disease: Recent Trends and Future Development.

Alzheimer's disease (AD) is the primary cause of dementia and is characterized by the death of brain cells due to the accumulation of insoluble amyloid plaques, hyperphosphorylation of tau protein, and the formation of neurofibrillary tangles within the cells. AD is also associated with other pathologies such as neuroinflammation, dysfunction of synaptic connections and circuits, disorders in mitochondrial function and energy production, epigenetic changes, and abnormalities in the vascular system. Despite extensive research conducted over the last hundred years, little is established about what causes AD or how to effectively treat it. Given the severity of the disease and the increasing number of affected individuals, there is a critical need to discover effective medications for AD. The US Food and Drug Administration (FDA) has approved several new drug molecules for AD management since 2003, but these drugs only provide temporary relief of symptoms and do not address the underlying causes of the disease. Currently, available medications focus on correcting the neurotransmitter disruption observed in AD, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate (NMDA) receptor, which temporarily alleviates the signs of dementia but does not prevent or reverse the course of AD. Research towards disease-modifying AD treatments is currently underway, including gene therapy, lipid nanoparticles, and dendrimer-based therapy. These innovative approaches aim to target the underlying pathological processes of AD rather than just managing the symptoms. This review discusses the novel aspects of pathogenesis involved in the causation of AD of AD and in recent developments in the therapeutic armamentarium for the treatment of AD such as gene therapy, lipid nanoparticles, and dendrimer-based therapy, and many more.

Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures

Alzheimer’s Disease (AD) is characterized by the accumulation of extracellular amyloid-β (Aβ) as well as CNS and systemic inflammation. Microglia, the myeloid cells resident in the CNS, use microRNAs to rapidly respond to inflammatory signals. MicroRNAs (miRNAs) modulate inflammatory responses in microglia, and miRNA profiles are altered in Alzheimer’s disease (AD) patients. Expression of the pro-inflammatory miRNA, miR-155, is increased in the AD brain. However, the role of miR-155 in AD pathogenesis is not well-understood. We hypothesized that miR-155 participates in AD pathophysiology by regulating microglia internalization and degradation of Aβ. We used CX3CR1CreER/+ to drive-inducible, microglia-specific deletion of floxed miR-155 alleles in two AD mouse models. Microglia-specific inducible deletion of miR-155 in microglia increased anti-inflammatory gene expression while reducing insoluble Aβ1-42 and plaque area. Yet, microglia-specific miR-155 deletion led to early-onset hyperexcitability, recurring spontaneous seizures, and seizure-related mortality. The mechanism behind hyperexcitability involved microglia-mediated synaptic pruning as miR-155 deletion altered microglia internalization of synaptic material. These data identify miR-155 as a novel modulator of microglia Aβ internalization and synaptic pruning, influencing synaptic homeostasis in the setting of AD pathology.

Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides, and Aβ oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with Aβ peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods—mainly spectroscopy and imaging techniques—to characterize Aβ/Ni(II) interactions in vitro, for different Aβ variants: Aβ(1–40), Aβ(1–40)(H6A, H13A, H14A), Aβ(4–40), and Aβ(1–42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length Aβ monomers. Equimolar amounts of Ni(II) ions retard Aβ aggregation and direct it towards non-structured aggregates. The His6, His13, and His14 residues are implicated as binding ligands, and the Ni(II)·Aβ binding affinity is in the low µM range. The redox-active Ni(II) ions induce formation of dityrosine cross-links via redox chemistry, thereby creating covalent Aβ dimers. In aqueous buffer Ni(II) ions promote formation of beta sheet structure in Aβ monomers, while in a membrane-mimicking environment (SDS micelles) coil–coil helix interactions appear to be induced. For SDS-stabilized Aβ oligomers, Ni(II) ions direct the oligomers towards larger sizes and more diverse (heterogeneous) populations. All of these structural rearrangements may be relevant for the Aβ aggregation processes that are involved in AD brain pathology.

Aza-Residue Modulation of Cyclic d,l-α-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity.

Transient soluble oligomers of amyloid-β (Aβ) are considered among the most toxic species in Alzheimer's disease (AD). Soluble Aβ oligomers accumulate early prior to insoluble plaque formation and cognitive impairment. The cyclic d,l-α-peptide CP-2 (1) self-assembles into nanotubes and demonstrates promising anti-amyloidogenic activity likely by a mechanism involving engagement of soluble oligomers. Systematic replacement of the residues in peptide 1 with aza-amino acid counterparts was performed to explore the effects of hydrogen bonding on propensity to mitigate Aβ aggregation and toxicity. Certain azapeptides exhibited improved ability to engage, alter the secondary structure, and inhibit aggregation of Aβ. Moreover, certain azapeptides disassembled preformed Aβ fibrils and protected cells from Aβ-mediated toxicity. Substitution of the l-norleucine3 and d-serine6 residues in peptide 1 with aza-norleucine and aza-homoserine provided, respectively, nontoxic [azaNle3]-1 (4) and [azaHse6]-1 (7), that significantly abated symptoms in a transgenic Caenorhabditis elegans AD model by decreasing Aβ oligomer levels.

The Vascular-Immune Hypothesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating and irreversible neurodegenerative disorder with unknown etiology. While its cause is unclear, a number of theories have been proposed to explain the pathogenesis of AD. In large part, these have centered around potential causes for intracerebral accumulation of beta-amyloid (βA) and tau aggregates. Yet, persons with AD dementia often exhibit autopsy evidence of mixed brain pathologies including a myriad of vascular changes, vascular brain injuries, complex brain inflammation, and mixed protein inclusions in addition to hallmark neuropathologic lesions of AD, namely insoluble βA plaques and neurofibrillary tangles (NFTs). Epidemiological data demonstrate that overlapping lesions diminish the βA plaque and NFT threshold necessary to precipitate clinical dementia. Moreover, a subset of persons who exhibit AD pathology remain resilient to disease while other persons with clinically-defined AD dementia do not exhibit AD-defining neuropathologic lesions. It is increasingly recognized that AD is a pathologically heterogeneous and biologically multifactorial disease with uncharacterized biologic phenomena involved in its genesis and progression. Here, we review the literature with regard to neuropathologic criteria and incipient AD changes, and discuss converging concepts regarding vascular and immune factors in AD.

(Gd3+) Complexation with oligopeptide (SFVG) and amyloid peptide (Aβ13–23) in aqueous solution by NMR spectroscopy

Gadolinium (III) ion, which belongs to the subgroup of transition metal ions, has practical importance for magnetic resonance imaging (MRI) with contrast. The accumulation of complexes of transition metal ions with amyloid peptides in the human body leads to the formation of insoluble plaques, which are presumably-one of the causes of Alzheimer's disease. This paper presents the results of studying the interaction of the gadolinium (III) ion with a fragment of amyloid protein Aβ40 in aqueous solutions using nuclear magnetic resonance spectroscopy. Tetrapeptide (SFVG) was used as the simplified model of metal-peptide interaction research. Beta-amyloid peptide (Aβ13-23) was chosen as the amyloid protein Aβ40 fragment model. Analysis of 1H NMR spectra revealed that the interaction exists for both types of molecules. It was also suggested the possible location of gadolinium (III) ion in the studied molecules.

Early diagnosis and treatment of Alzheimer’s disease by targeting toxic soluble Aβ oligomers

Transient soluble oligomers of amyloid-β (Aβ) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer's disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1) self-assemble into cross β-sheet nanotubes, react with early Aβ species (1-3 mers), and inhibit Aβ aggregation and toxicity in stoichiometric concentrations, in vitro. Employing a semicarbazide as an aza-glycine residue with an extra hydrogen-bond donor to tune nanotube assembly and amyloid engagement, [azaGly6]-1 inhibited Aβ aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly6]-1 and Aβ42 residues F19 and F20, which are pivotal for early dimerization and aggregation. In an AD mouse model, brain positron emission tomography (PET) imaging using stable 64Cu-labeled (aza)peptide tracers gave unprecedented early amyloid detection in 44-d presymptomatic animals. No tracer accumulation was detected in the cortex and hippocampus of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the thalamus, from where Aβ oligomers may spread to other brain parts with disease progression. Compared with standard 11C-labeled Pittsburgh compound-B (11C-PIB), which binds specifically fibrillar Aβ plaques, 64Cu-labeled (aza)peptide gave superior contrast and uptake in young mouse brain correlating with Aβ oligomer levels. Effectively crossing the blood-brain barrier (BBB), peptide 1 and [azaGly6]-1 reduced Aβ oligomer levels, prolonged lifespan of AD transgenic Caenorhabditis elegans, and abated memory and behavioral deficits in nematode and murine AD models. Cyclic (aza)peptides offer novel promise for early AD diagnosis and therapy.

Quantitative systems pharmacology model of the amyloid pathway in Alzheimer's disease: Insights into the therapeutic mechanisms of clinical candidates.

Despite considerable investment into potential therapeutic approaches for Alzheimer's disease (AD), currently approved treatment options are limited. Predictive modeling using quantitative systems pharmacology (QSP) can be used to guide the design of clinical trials in AD. This study developed a QSP model representing amyloid beta (Aβ) pathophysiology in AD. The model included mechanisms of Aβ monomer production and aggregation to form insoluble fibrils and plaques; the transport of soluble species between the compartments of brain, cerebrospinal fluid (CSF), and plasma; and the pharmacokinetics, transport, and binding of monoclonal antibodies to targets in the three compartments. Ordinary differential equations were used to describe these processes quantitatively. The model components were calibrated to data from the literature and internal studies, including quantitative data supporting the underlying AD biology and clinical data from clinical trials for anti-Aβ monoclonal antibodies (mAbs) aducanumab, crenezumab, gantenerumab, and solanezumab. The model was developed for an apolipoprotein E (APOE) ɛ4 allele carrier and tested for an APOE ɛ4 noncarrier. Results indicate that the model is consistent with data on clinical Aβ accumulation in untreated individuals and those treated with monoclonal antibodies, capturing increases in Aβ load accurately. This model may be used to investigate additional AD mechanisms and their impact on biomarkers, as well as predict Aβ load at different dose levels for mAbs with known targets and binding affinities. This model may facilitate the design of scientifically enriched and efficient clinical trials by enabling a priori prediction of biomarker dynamics in the brain and CSF.

Current and potential therapeutic strategies for transthyretin cardiac amyloidosis

Cardiac amyloidosis is a progressive disorder caused by the deposition of amyloid, abnormal proteins that aggregate to form insoluble plaques in the myocardium resulting in restrictive cardiomyopathy. The two most common subtypes of cardiac amyloidosis are immunoglobulin light chain (AL) and transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM). ATTR-CM can further be subdivided into two main categories, wild-type or hereditary TTR. TTR is a homotetrameric protein complex that is synthesized in the liver and is secreted into the circulation for retinol and vitamin A transfer. Genetic mutations in the TTR gene can disrupt the thermodynamic stability of the homotetrameric complex causing dissociation into monomers that, when taken up by the myocardium, will aggregate to form insoluble fibers. Though the mechanism of wild-type TTR is not fully elucidated, it is thought to be an age-related process. Myocardial uptake and aggregation of TTR monomeric subunits result in cytotoxicity, impaired cardiac function, and eventually heart failure. Historically, ATTR-CM had a poor prognosis, with no therapeutics available to specifically target ATTR-CM and treatment focused on managing symptoms and disease-related complications. In 2019, the FDA approved the first-in-class TTR stabilizer for ATTR-CM, which has led to improved outcomes. In recent years, several promising novel therapies have emerged which aim to target various points of the ATTR-CM amyloidogenic cascade. In this review, we discuss the mechanistic underpinnings of ATTR-CM, review current FDA-approved strategies for treatment, and highlight ongoing research efforts as potential therapeutic options in the future.

Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

During the early stages of Alzheimer’s disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β 1–42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble amyloid plaques. In a transgenic AD mouse model, we observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites corresponding to the dendritic domain where the earliest synaptic loss is detected in vivo. We also observed AMPK over-activation as well as increased fragmentation and loss of mitochondrial biomass in Ngn2-induced neurons derived from a new APPSwe/Swe knockin human ES cell line. We demonstrate that Aβ42o-dependent over-activation of the CAMKK2-AMPK kinase dyad mediates synaptic loss through coordinated phosphorylation of MFF-dependent mitochondrial fission and ULK2-dependent mitophagy. Our results uncover a unifying stress-response pathway causally linking Aβ42o-dependent structural remodeling of dendritic mitochondria to synaptic loss.