Interaction Of Aβ Research Articles

Heterotypic Interactions of Amyloid β and the Islet Amyloid Polypeptide Produce Mixed Aggregates with Non-Native Fibril Structure.

Amyloid aggregates are hallmarks of the pathology of a wide range of diseases, including type 2 diabetes (T2D) and Alzheimer's disease (AD). Much epidemiological and pathological evidence points to significant overlap between AD and T2D. Individuals with T2D have a higher likelihood of developing AD; moreover, colocalized aggregates of amyloid β (Aβ) and the islet amyloid polypeptide (IAPP), the two main peptides implicated in the formation of toxic amyloid aggregates in AD and T2D, have also been identified in the brain. However, how these peptides interact with each other is not well understood, and the structural facets of heterotypic mixed fibrils formed via such interactions remain elusive. Here we use atomic force microscopy augmented with infrared spectroscopy to probe the secondary structure of individual aggregates formed via heterotypic interactions of Aβ and IAPP and provide unequivocal direct evidence of mixed aggregates. Furthermore, we show that co-aggregation of the peptides from the monomeric stage leads to the formation of unique polymorphs, in which both peptides undergo structural deviation from their native states, whereas seeding with preformed IAPP fibrils leads to aggregates similar to native Aβ. These findings highlight how heterotypic interactions between amyloidogenic peptides can lead to polymorphic diversity proteinopathies.

Damage of the Phospholipid Bilayer by Aβ42 at Physiologically Relevant Peptide Concentrations.

Amyloid β (Aβ) aggregates are implicated in the pathology of several neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease, and damage to membranes is considered one of the pathology-related effects of Aβ. Experiments in vitro indicate that Aβ can damage these membranes; however, such experiments were performed at Aβ concentrations in the micromolar range, several orders above the physiologically relevant conditions. Our studies with Aβ42 in the low nanomolar concentrations did not reveal any damage to the supported lipid bilayer, questioning this membrane damage mechanism of Aβ. However, the phospholipid composition can be a factor contributing to the interaction of Aβ with the membrane. Therefore, in this study, we investigated the interaction of 50 nM Aβ42 with supported lipid bilayers composed of equimolar ratios of POPS and POPC at phospholipid concentrations of 0.1 and 0.25 mg/mL. Using atomic force microscopy (AFM), we observed that Aβ42 induced damage to bilayers at 0.1 mg/mL, characterized by forming defects that grew in size and number over time. The defects penetrate only the upper leaflet of the bilayer, but no such defects were observed at 0.25 mg/mL phospholipid concentrations. We additionally determined Young's modulus of these bilayers as a measure of stiffness, and these values were 6.9 ± 3.6 MPa and 16.6 ± 5.3 MPa for the 0.1 mg/mL and the 0.25 mg/mL bilayers, respectively. These findings suggest that Aβ42's ability to induce bilayer damage depends on membrane stiffness, with softer bilayers (0.1 mg/mL) being more susceptible to Aβ42-induced damage. The results are discussed and compared with models in which Aβ42 oligomers create localized membrane damage. The implication of the results to the mechanisms of the Aβ42 oligomer pathology is discussed.

Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE

APOE is a major genetic factor in late-onset Alzheimer’s disease (LOAD), with APOE4 increasing risk, APOE3 acting as neutral, and APOE2 offering protection. APOE also plays key role in lipid metabolism, affecting both peripheral and central systems, particularly in lipoprotein metabolism in triglyceride and cholesterol regulation. APOE2 is linked to Hyperlipoproteinemia type III (HLP), characterized by mixed hypercholesterolemia and hypertriglyceridemia due to impaired binding to Low-Density Lipoproteins receptors. To explore the impact of human APOE isoforms on LOAD and lipid metabolism, we developed Long-Evans rats with human APOE2, APOE3, or APOE4 in place of rat Apoe. These rats were crossed with those carrying a humanized App allele to express human Aβ, which is more aggregation-prone than rodent Aβ, enabling the study of human APOE-human Aβ interactions. In this study, we focused on 80-day-old adolescent rats to analyze early changes that may be associated with the later development of LOAD. We found that APOE2hAβ rats had the highest levels of APOE in serum and brain, with no significant transcriptional differences among isoforms, suggesting variations in protein translation or stability. Aβ43 levels were significantly higher in male APOE4hAβ rats compared to APOE2hAβ rats. However, no differences in Tau or phosphorylated Tau levels were observed across the APOE isoforms. Neuroinflammation analysis revealed lower levels of IL13, IL4 and IL5 in APOE2hAβ males compared to APOE4hAβ males. Neuronal transmission and plasticity tests using field Input-Output (I/O) and long-term potentiation (LTP) recordings showed increased excitability in all APOE-carrying rats, with LTP deficits in APOE2hAβand APOE4hAβ rats compared to ApoehAβ and APOE3hAβ rats. Additionally, a lipidomic analysis of 222 lipid molecular species in serum samples showed that APOE2hAβ rats displayed elevated triglycerides and cholesterol, making them a valuable model for studying HLP. These rats also exhibited elevated levels of phosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, and lysophosphatidylcholine. Minimal differences in lipid profiles between APOE3hAβ and APOE4hAβ rats reflect findings from mouse models. Future studies will include comprehensive lipidomic analyses in various CNS regions and at older ages to further validate these models and explore the effects of APOE isoforms on lipid metabolism in relation to AD pathology.

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.

Interplay between glypican-1, amyloid-β and tau phosphorylation in human neural stem cells

IntroductionAlzheimer’s disease (AD) is characterized by accumulation of amyloid beta (Aβ) and hyperphosphorylated tau (Tau-P) in the brain. Aβ enhances the activity of kinases involved in the formation of Tau-P. Phosphorylation at Thr 181 determines the propagation of multiple tau phosphorylations. Aβ is derived from the amyloid precursor protein (APP). Cleavage of APP by β-secretase also initiates release of heparan sulfate (HS) from the proteoglycan glypican-1 (GPC1). ObjectivesIn this study, we have explored possible connections between GPC1 expression, HS release, APP processing and Tau-P formation in human neural stem cells. MethodsGPC1 formation was suppressed by using CRISPR/Cas9 and increased by using a vector encoding GPC1. HS release from GPC1 was increased by growing cells in medium containing Arg and ascorbate. Effects were monitored by immunofluorescence microscopy and slot immunoblotting using antibodies/antisera recognizing Aβ, GPC1, HS released from GPC1, total Tau, and Tau phosphorylated at Thr-181, 217 or 231. The latter have been used as blood biomarkers for AD. ResultsSuppression of GPC1 expression resulted in increased phosphorylation at Thr 181 and Thr 217. When GPC1 was overexpressed, phosphorylation at Thr 217 decreased. Stimulation of HS release from GPC1 diminished tau phosphorylation at all of the three Thr positions, while expression of GPC1 was unaffected. Simultaneous stimulation of HS release and APP processing by the cytokine TNF-α also suppressed tau phosphorylation. ConclusionThe increased release of GPC1-derived HS may interfere with Aβ formation and/or Aβ interaction with tau.

The Effects of Sevoflurane and Aβ Interaction on CA1 Dendritic Spine Dynamics and MEGF10-Related Astrocytic Synapse Engulfment.

General anesthetics may accelerate the neuropathological changes related to Alzheimer's disease (AD), of which amyloid beta (Aβ)-induced toxicity is one of the main causes. However, the interaction of general anesthetics with different Aβ-isoforms remains unclear. In this study, we investigated the effects of sevoflurane (0.4 and 1.2 maximal alveolar concentration (MAC)) on four Aβ species-induced changes on dendritic spine density (DSD) in hippocampal brain slices of Thy1-eGFP mice and multiple epidermal growth factor-like domains 10 (MEGF10)-related astrocyte-mediated synaptic engulfment in hippocampal brain slices of C57BL/6 mice. We found that both sevoflurane and Aβ downregulated CA1-dendritic spines. Moreover, compared with either sevoflurane or Aβ alone, pre-treatment with Aβ isoforms followed by sevoflurane application in general further enhanced spine loss. This enhancement was related to MEGF10-related astrocyte-dependent synaptic engulfment, only in AβpE3 + 1.2 MAC sevoflurane and 3NTyrAβ + 1.2 MAC sevoflurane condition. In addition, removal of sevoflurane alleviated spine loss in Aβ + sevoflurane. In summary, these results suggest that both synapses and astrocytes are sensitive targets for sevoflurane; in the presence of 3NTyrAβ, 1.2 MAC sevoflurane alleviated astrocyte-mediated synaptic engulfment and exerted a lasting effect on dendritic spine remodeling.

Rational fusion design inspired by cell-penetrating peptide: SS31/S-14 G Humanin hybrid peptide with amplified multimodal efficacy and bio-permeability for the treatment of Alzheimer's disease

Alzheimer's disease is a neurodegenerative disease induced by multiple interconnected mechanisms. Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology. However, clinical translation of peptide drugs is greatly hampered by their low permeability into brain. Herein, a hybrid peptide HNSS is generated by merging two therapeutic peptides (SS31 and S-14 G Humanin (HNG)), using a different approach from the classical shuttle-therapeutic peptide conjugate design. HNSS demonstrated increased bio-permeability, with a 2-fold improvement in brain distribution over HNG, thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides. HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting, ROS scavenging and p-STAT3 activation. Meanwhile, HNSS with increased Aβ affinity greatly inhibited Aβ oligomerization/fibrillation, and interrupted Aβ interaction with neuron/microglia by reducing neuronal mitochondrial Aβ deposition and promoting microglial phagocytosis of Aβ. In 3× Tg-AD transgenic mice, HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance. This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification, providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease.

Cornuside ameliorates cognitive impairments via RAGE/TXNIP/NF-κB signaling in Aβ1-42 induced Alzheimer's disease mice.

Cornuside has been discovered to improve learning and memory in AD mice, however, its underlying mechanism was not fully understood. In the present study, we established an AD mice model by intracerebroventricular injection of Aβ1-42, which were treated with cornuside (3, 10, 30mg/kg) for 2weeks. Cornuside significantly ameliorated cognitive function of AD mice in series of behavioral tests, including Morris water maze test, nest building test, novel object recognition test and step-down test. Additionally, cornuside could attenuate neuronal injury, and promote cholinergic synaptic transmission by restoring the level of acetylcholine (ACh) via inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as facilitating choline acetyltransferase (ChAT). Furthermore, cornuside inhibited oxidative stress levels amplified as decreased malondialdehyde (MDA), by inhibiting TXNIP expression, improving total anti-oxidative capacity (TAOC), raising activities of superoxide dismutase (SOD) and catalase (CAT). Cornuside also reduced the activation of microglia and astrocytes, decreased the level of proinflammatory factors TNF-α, IL-6, IL-1β, iNOS and COX2 via interfering RAGE-mediated IKK-IκB-NF-κB phosphorylation. Similar anti-oxidative and anti-inflammatory effects were also found in LPS-stimulated BV2 cells via hampering RAGE-mediated TXNIP activation and NF-κB nuclear translocation. Virtual docking revealed that cornuside could interact with the active pocket of RAGE V domain directly. In conclusion, cornuside could bind to the RAGE directly impeding the interaction of Aβ and RAGE, and cut down the expression of TXNIP inhibiting ROS production and oxidative stress, as well as hamper NF-κB p65 mediated the inflammation.

Conformational analysis of lipid membrane mimetics modified with Aβ42 peptide by Raman spectroscopy and computer simulations

Peptide-lipid interactions play an important role in maintaining the integrity and function of the cell membrane. Even slight changes in these interactions can induce the development of various diseases. Specifically, peptide misfolding and aggregation in the membrane is considered to be one of the triggers of Alzheimer’s disease (AD), however its exact mechanism is still unclear. To this end, an increase of amyloid-beta (Aβ) peptide concentration in the human brain is widely accepted to gradually produce cytotoxic Aβ aggregates (plaques). These plaques initiate a sequence of pathogenic events ending up in observable symptoms of dementia. Understanding the mechanism of the Aβ interaction with cells is crucial for early detection and prevention of Alzheimer’s disease. Hence, in this work, a comprehensive Raman analysis of the Aβ42 conformational dynamics in water and in liposomes and lipodiscs that mimic the membrane system is presented. The obtained results show that the secondary structure of Aβ42 in liposomes is dominated by the α–helix conformation, which remains stable over time. However, it comes as a surprise to reveal that the lipodisc environment induces the transformation of the Aβ42 secondary structure to a β-turn/random coil. Our Raman spectroscopy findings are supported with molecular dynamics (MD) and density functional theory (DFT) simulations, showing their good agreement. Communicated by Ramaswamy H. Sarma

The Influence of Lipid Electric Charge on the Binding of Aβ(1-42) Amyloid Peptide to Bilayers in the Liquid-Ordered State.

The amyloidogenic Aβ peptides are widely considered as a pathogenic agent in Alzheimer's disease. Aβ(1-42) would form aggregates of amyloid fibrils on the neuron plasma membranes, thus perturbing neuronal functionality. Conflicting data are available on the influence of bilayer order on Aβ(1-42) binding to membranes. In the present study, a biophysical approach was used in which isothermal calorimetry and surface pressure measurements were applied to explore the interaction of Aβ(1-42) in either monomeric, oligomeric, or fibrillar form with model membranes (bilayers or monolayers) in the liquid-ordered state that were either electrically neutral or negatively charged. In the latter case, this contained phosphatidic acid, cardiolipin, or ganglioside. The calorimetric studies showed that Aβ(1-42) fibrils, oligomers, and monomers could bind and/or be inserted into bilayers, irrespective of electric charge, in the liquid-ordered state, except that monomers could not interact with electrically neutral bilayers. The monolayer studies in the Langmuir balance demonstrated that Aβ(1-42) aggregation hindered peptide insertion into the monolayer, hindered insertion in the decreasing order of monomer > oligomer > fibril, and that lipid composition did not cause large differences in insertion, apart from a slight facilitation of monomer and oligomer insertion by gangliosides.

Proteomic analysis identifies HSP90AA1, PTK2B, and ANXA2 in the human entorhinal cortex in Alzheimer's disease: Potential role in synaptic homeostasis and Aβ pathology through microglial and astroglial cells.

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder worldwide, is clinically characterized by cognitive deficits. Neuropathologically, AD brains accumulate deposits of amyloid-β (Aβ) and tau proteins. Furthermore, these misfolded proteins can propagate from cell to cell in a prion-like manner and induce native proteins to become pathological. The entorhinal cortex (EC) is among the earliest areas affected by tau accumulation along with volume reduction and neurodegeneration. Neuron-glia interactions have recently come into focus; however, the role of microglia and astroglia in the pathogenesis of AD remains unclear. Proteomic approaches allow the determination of changes in the proteome to better understand the pathology underlying AD. Bioinformatic analysis of proteomic data was performed to compare ECs from AD and non-AD human brain tissue. To validate the proteomic results, western blot, immunofluorescence, and confocal studies were carried out. The findings revealed that the most disturbed signaling pathway was synaptogenesis. Because of their involvement in synapse function, relationship with Aβ and tau proteins and interactions in the pathway analysis, three proteins were selected for in-depth study: HSP90AA1, PTK2B, and ANXA2. All these proteins showed colocalization with neurons and/or astroglia and microglia and with pathological Aβ and tau proteins. In particular, ANXA2, which is overexpressed in AD, colocalized with amoeboid microglial cells and Aβ plaques surrounded by astrocytes. Taken together, the evidence suggests that unbalanced expression of HSP90AA1, PTK2B, and ANXA2 may play a significant role in synaptic homeostasis and Aβ pathology through microglial and astroglial cells in the human EC in AD.

Transformation of non-neuritic into neuritic plaques during AD progression drives cortical spread of tau pathology via regenerative failure

Extracellular amyloid-β (Aβ) plaques and intracellular aggregates of tau protein in form of neurofibrillary tangles (NFT) are pathological hallmarks of Alzheimer’s disease (AD). The exact mechanism how these two protein aggregates interact in AD is still a matter of debate. Neuritic plaques (NP), a subset of Aβ plaques containing dystrophic neurites (DN), are suggested to be unique to AD and might play a role in the interaction of Aβ and tau. Quantifying NP and non-NP in postmortem brain specimens from patients with increasing severity of AD neuropathological changes (ADNC), we demonstrate that the total number of Aβ plaques and NP increase, while the number of non-NP stagnates. Furthermore, investigating the correlation between NP and NFT, we identified unexpected brain region-specific differences when comparing cases with increasingly more severe ADNC. In neocortical regions NFT counts increase in parallel with NP counts during the progression of ADNC, while this correlation is not observed in hippocampus. These data support the notion that non-NP are transformed into NP during the progression of ADNC and indicate that NP might drive cortical NFT formation. Next, using spatial transcriptomics, we analyzed the gene expression profile of the microenvironment around non-NP and NP. We identified an upregulation of neuronal systems and Ca-dependent event pathways around NP compared to non-NP. We speculate that the upregulation of these transcripts may hint at a compensatory mechanism underlying NP formation. Our studies suggest that the transformation of non-NP to NP is a key event in ADNC progression and points to regenerative failure as a potential driving force of this process.

Exploration of novel biomarkers for neurodegenerative diseases using ligand‐binding assays

AbstractBackgroundNeurodegeneration is a complex area involving multiple pathways and often has a long prodromal phase. Reliable biomarkers are needed to allow earlier diagnosis, monitoring of the disease progression, and studying the impact of therapeutic approaches.MethodTherefore, a screening was performed by Sciomics GmbH to identify potential protein biomarkers. The most promising analytes were selected, including cluster of differentiation 14 (CD14), osteopontin (OPN), vascular endothelial growth factor A (VEGF‐A), cancer antigen 15‐3 (CA15‐3) and carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM‐1). Using quantitative ligand‐binding assays based on fluorescence or electrochemiluminescence these analytes were investigated regarding up‐ or downregulation in the presence of Alzheimer´s disease (AD), Parkinson´s disease (PD), Multiple Sclerosis (MS) or Amyotrophic Lateral Sclerosis (ALS) compared to healthy patients.ResultThe quantitative assays confirmed the screening in that CD14 levels were elevated in cerebrospinal fluid (CSF) of AD patients and that OPN levels were increased in CSF of PD patients. In addition, the following significant changes were observed: OPN was elevated in plasma of PD and MS patients, while it was decreased in CSF of MS patients. VEGF‐A levels were increased in the plasma of ALS patients and decreased in CSF of MS patients.ConclusionIncreased CD14 levels in AD CSF are in agreement with studies suggesting that CD14, a co‐receptor of toll like receptor 4 (TLR4) expressed on the surface of e.g. microglia, might mediate the interaction of fibrillar Aβ to TLR4 and thus induce inflammation. OPN has already been shown to be increased in CSF and blood of PD patients previously and it is suggested to be involved in PD pathogenesis due to its role in oxidative stress, apoptosis, mitochondrial dysfunction, and cytokine regulation. Other studies have shown increased levels of OPN in plasma of MS patients potentially due to its expression in activated T‐cells. However, some studies also show increased MS CSF levels in contrast to our findings, where OPN levels are lower in MS CSF. Literature data for VEGF‐A is more conflicting possibly due to different assays detecting different isoforms. To further solidify these findings, large‐scale analyses using well characterized samples should be done in the future.

Identification of genes and blood co‐expression networks associated with cerebrovascular neuroimaging phenotypes

AbstractBackgroundA hallmark of Alzheimer’s disease is amyloid‐β (Aβ) deposition in the brain parenchyma as senile plaques which Aß frequently accompanies in the cerebral vasculature as cerebral amyloid angiopathy (CAA). Previous studies demonstrated that the cerebrovascular system is essential for Aβ clearance and interactions exist between cerebrovascular disease and AD. Neuroimaging data, including measures on small vessel disease, amyloid deposits, and microhemorrhages (MCH), can reflect both cerebrovascular disease and AD pathology, thereby serving as intermediate phenotypes of both conditions. We aim to identify genes and co‐expression networks in blood associated with these neuroimaging endophenotypes and the biological pathways enriched in these perturbed transcriptional networks.MethodWe conducted differential gene expression and Weighted Gene Co‐Expression Network analyses (WGCNA) on blood RNA sequencing data of 407 participants from the longitudinally followed Mayo Clinic Study of Aging cohort. The neuroimaging phenotypes include MCH, infarction, and amyloid deposits measured by Pittsburgh compound B positron emission tomography (PiB PET).ResultWGCNA analysis showed a nominally significant association (p<0.05) between several module eigengenes (MEs) and MCH and PiB PET. One module, M42, remained significantly associated with PiB PET after Bonferroni correction for all 43 modules tested. Pathway enrichment analysis of M42 identified two significant pathways (FDR‐adjusted p<0.05) including phosphodiesterase I activity and IgE binding. These pathways contain genes such as MS4A2 encoding the high‐affinity IgE receptor involved in the immune response. Similarly, ENPP2 in the phosphodiesterase I activity pathway represents an additional candidate gene previously implicated in Alzheimer’s disease.ConclusionWe generated co‐expression networks and identified one network module with a statistically significant association between brain amyloid deposits and blood transcriptome data. Further investigations of this network and its enriched pathways are necessary to understand their roles in amyloidosis, CAA, and neurodegeneration. Future studies will include seeking replication of these results in other datasets. Such studies can help elucidate the biological mechanisms of pathogenesis of cerebrovascular damage and amyloid deposits. In addition, in a clinical setting, blood levels of transcripts discovered in this study may serve as predictive or diagnostic biomarkers with mechanistic implications.

Inter‐network connectivity of early Aβ and tau‐seeded functional networks is associated with longitudinal tau accumulation in at‐risk cognitively normal older adults

AbstractBackgroundFunctional connectivity (FC) between networks may be related to Aβ and tau interactions in preclinical Alzheimer’s disease (AD). Here, we investigated associations between inter‐network FC of early Aβ and tau‐seeded networks, APOEe4, global Aβ, and longitudinal tau accumulation in cognitively healthy older adults (OA).MethodVoxel‐wise PiB‐PET and FTP‐PET OA images were ordered by increasing pathology burden and iteratively compared to a reference set of young adult (YA) PET images. Peak voxels of the earliest significant differences were matched to Brainnetome ROIs and used to construct separate Aβ and tau‐seeded networks within a group average YA FC matrix (Figure 1). Next, the average inter‐network FC between all node pairs between the networks was calculated in OA (n = 60; aged 77.6±5.5). Longitudinal FTP slopes of the entorhinal cortex (EC) and inferior temporal gyrus (ITG) were estimated using linear mixed effects models. Linear regression was used to assess relationships between baseline inter‐network FC, APOEe4 status, baseline global PiB, and both a prior ROI and voxel‐wise FTP slopes.ResultIn all OA, inter‐network FC was not associated with baseline global PIB (t(58) = ‐0.23, p = 0.82), EC FTP slope (t(58) = 0.49, p = 0.63), or ITG FTP slope (t(58) = ‐1.45, p = 0.15). There was a significant interaction between baseline global PiB status and inter‐network FC where FC was negatively associated with ITG FTP slope in PiB+ participants (t(56) = ‐2.01, p = 0.04; Figure 2A). There was also a significant interaction between APOEe4 status and inter‐network FC in predicting ITG FTP slope with a negative relationship only in e4 carriers (t(56) = ‐3.19, p = 0.003; Figure 2B). Voxel‐wise analyses revealed significant negative relationships between inter‐network FC and FTP slope in the left fusiform gyrus and ITG in PiB+ participants and e4 carriers, respectively (Figure 2C‐D).ConclusionLower baseline inter‐network FC of early Aβ and tau‐seeded networks was associated with greater longitudinal tau accumulation outside of the medial temporal lobe (MTL) in cognitively normal OA with higher AD risk (i.e., elevated Aβ or APOEe4). Our results suggest that this network disruption is associated with faster rates of tau accumulation outside of the MTL, possibly reflecting a later stage in the preclinical progression to AD.

Examining Complex Relationships among Cerebrovascular, β‐Amyloid, Tau and Cognitive Measures in a Cognitively Unimpaired Late‐Middle Aged Sample

AbstractBackgroundRecent research linking vascular risk with promotion of tau pathology in the inferior temporal cortex (ITC) suggests a potential mechanism connecting cerebrovascular risk to AD pathology and cognitive decline among cognitively unimpaired (CU) individuals (Yau et al, 2022).We used MRI White Matter Hyperintensity (WMH), a neuroimaging marker of chronic cerebral small‐vessel disease/cerebrovascular disease, to further elucidate longitudinal relationships between cerebrovascular risk, PET AD pathological burden, and cognition.MethodWe examined baseline CU late middle‐aged adults from the University of Wisconsin’s Alzheimer’s disease research cohorts. β‐Amyloid burden was measured with 11C‐Pittsburgh compound B (“PiB”; DVR derived from a 0‐70 min dynamic PET scan; PET A+ threshold∼1.16 DVR/∼CL 17). Cerebrovascular risk was quantified using WMH volumes (T2‐FLAIR images; SPM Lesion Segmentation Tool). Tau burden was measured with florquinitau PET (MK6240 SUVR from 70‐90 min post‐injection). Tau outcomes included bilateral volume‐weighted averages for ITC, Medial temporal lobe (MTL) and Meta‐temporal (MTC) composites. Biomarker values were z‐transformed relative to CU/PET A‐ values. Random intercept models examined interactive effects of baseline WMH and Aβ levels on longitudinal tau (covarying baseline tau age, sex, APOE ε4 count). We modeled time two ways: years since baseline PiB (TimePiB1; replicating Yau, et al models); and, in parallel models, amyloid duration (years) at tau scans was substituted for years since PiB1 in the A+ subset (TimePiB1/PiB+). We also used LME to examine Aβ, WMH, and time interactions in longitudinal cognition (PACC3 and Digit Symbol Substitution).ResultThe mean(SD) tau baseline age was 67.9(6.8) years (sample details in Table1). The most parsimonious models using TimePiB1 included WMH*Aβ*Time for ITC and MTC and WMH*Aβ for MTL. Patterns showed a synergistic effect of WMH and Aβ on tau accumulation that was attenuated using TimePiB1/PiB+ where the most parsimonious models included Aβ_status*TimePiB1/PiB+ (ITC, MTC) or WMH*Aβ_status*TimePiB1/PiB+ (MTL; Figure1). AICc model fits were substantially better using TimePiB1/PiB+. Both Aβ and WMH contributed to cognitive trajectories (Figure2).ConclusionAlthough cerebrovascular risk’s apparent contribution to tau accumulation varied depending on how time was modeled, results suggest that cerebrovascular risk may complement imaging biomarkers in assessing risk of tau accumulation and cognitive decline in preclinical Alzheimer disease.

Antagonistic Amyloid‐β and tau interactions with T1‐weighted/T2‐weighted magnetic resonance ratio in Alzheimer’s disesase continuum

AbstractBackgroundTau protein has been reported as a major cause of neurodegeneration in Alzheimer’s disease (AD) continuum. Decrease of T1‐weighted/T2‐weighted magnetic resonace (MR) ratio has been proposed as a measure of demyelination related to neurodegeneration, but some previous researches showed contradictory increase in several brain regions, which was considered as the effecs of other microstructures such as the amyloid‐related iron deposition. Therefore, amyloid β and tau proteins appear to affect the T1w/T2w ratio antagonistically, making their relationship need to be elucidated in order to unambiguously interpret the ratio.MethodWe obtained 221 individuals which include T1‐ and T2‐weighted MR images, and 18F‐florbetapir‐ and 18F‐flortaucipir‐PET images from ADNI. The subjects were then divided into four subgroups based on the status of global Aβ and tau accumulation amount: A‐T‐, A‐T+, A+T‐, and A+T+. We determined positive amyloid status(A+) as global Aβ PET SUVR > 1.11. When determining tau positivity, we used entorhinal cortex (EC) as the earliest tau accumulation region to selectively include tau‐negative individuals while amyloid is being presented. Group differences in regional T1w/T2w ratio values were evaluated.ResultWe found significant group differences in various cortical regions, but also observed distinct effects of Aβ and tau for the T1w/T2w difference. First of all, Aβ and tau affect the T1w/T2w ratio in an opposite direction. A+ individuals have greater T1w/T2w ratio values across wide cortical regions compared to A‐ individuals for both T‐ and T+ groups. However, A‐T+ groups have smaller T1w/T2w ratio values than A‐T‐ groups, while the significant group difference was observed across relatively few cortical regions. Second, Aβ has stronger effect on the T1w/T2w ratio than tau. Specifically, the group difference between A+T+ and A+T‐ shows that Aβ increase the ratio values more strongly than tau reduces the ratio values due to greater accumulation of Aβ in the A+T+ than A+T‐.ConclusionIn this work, we observed the antagonistic interaction of Aβ and tau with T1w/T2w ratio, while more interestingly, we also found that Aβ causes high T1w/T2w ratio, more than tau causes demyelination, followed by lowering T1w/T2w ratio.

Clinical Manifestations.

In the present study, we investigated differences in amyloid (Aβ) burden and personality traits in cognitively-select older adults compared to average-functioning older adults. Conscientiousness, in particular, has been linked to Alzheimer's Disease (AD) pathology, and we hypothesized that adults who were high in cognition would exhibit enhanced conscientiousness. Of additional interest was whether high functioning older adults in the Dallas Lifespan Brain Study would evidence reduced AD pathology. We tested 285 cognitively-normal participants (ages 55-90) and collected conscientiousness scores using the Revised NEO Personality Inventory (NEO-PI-R). Participants also underwent PET imaging with radiotracer AV-45, 18F-Florbetapir, a radiotracer that is used to measure Aβ protein in the brain. Mean cortical SUVR was computed across 8 cortical regions of interest, normalized to cerebellar gray matter. In addition, participants completed a cognitive battery, underwent an MRI scan, and completed self-reports for depression and fitness. We designated those participants scoring at or above the mean episodic memory of a middle-aged (ages 35-54) reference group, as "cognitively-select" (N = 69), and those scoring below the mean, as "cognitively-normal" (N = 216). Dependent variables of interest included global and regional amyloid (Aβ), cortical morphometry, depression, fitness, conscientiousness, and various cognitive measures. Cognitively select participants were younger (p = .043), more educated (p = .021), and had higher positive personality traits, including self-discipline (p = .01), openness to ideas (p = .013), and competence (p = .015), compared to cognitively-normal. Although the groups did not differ in global Aβ pathology load (p = .083), cognitively select exhibited less pathology in specific regions including lateral temporal areas (p = .049). Regression analysis controlling for sex, age, education, and MMSE, revealed a significant group by global Aβ interaction on fluid ability (p = .034), where greater Aβ load predicted lower scores in cognitively normal older adults only. These findings provide evidence that cognitively privileged adults show resistance to decline across many domains and demonstrate resilience to amyloid pathology. Discussion will focus on longitudinal change in amyloid accumulation, cortical thinning, and cognitive decline, as well as the concept of reserve.

A genome‐wide association study of LATE‐NC (limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change) reveals a distinct genetic architecture

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is the third leading cause of late‐life dementia. However, its pathophysiology remains largely unknown, and the relationship of LATE‐NC with Alzheimer’s disease (AD) pathology and frontotemporal lobar degeneration‐TDP (FTLD‐TDP) remains unclear. To address this knowledge gap, we performed a genome‐wide association study (GWAS) of LATE‐NC.MethodDeceased participants of European ancestry from the Religious Orders Study, the Rush Memory and Aging Project (ROSMAP, n = 1,379), and the Adult Changes in Thought study (ACT, n = 459) were included in our study. The primary phenotypes were LATE‐NC burden (a multi‐regional semi‐quantitative TDP‐43 composite, continuous) in ROSMAP, and the presence/absence of LATE‐NC (binary) in ACT, assessed with post‐mortem TDP‐43 immunohistochemistry. Quantitative amyloid‐β (Aβ) and paired helical filament tau (PHFtau) burden were also examined in ROSMAP. GWAS was performed using linear (ROSMAP) or logistic (ACT) additive models. We controlled age, sex, genotyping platforms, and the first three genotype principal components. Sample size‐weighted GWAS meta‐analysis (total n = 1,838) was performed by combining p‐values considering the direction of the association. Confounding and moderating effects of AD pathology on LATE‐NC risk variants were examined in ROSMAP.ResultWe observed two genome‐wide significant risk loci (p<5.0×10−8) in APOE (ε4) and SHANK2 (s146617441G, allele frequency 0.021). In ROSMAP, APOE ε4 was associated with higher LATE‐NC burden after controlling for quantitative Aβ and PHFtau (beta = 0.27, p = 7.3×10−6), and the APOE ε4 – LATE‐NC association was present in the subgroup without detectable Aβ (n = 170, beta = 0.50, p = 0.025). rs146617441G was not directly associated with quantitative Aβ or tau. Instead, rs146617441G×Aβ interaction term was associated with higher LATE‐NC burden (beta = 0.25, p = 0.032), suggesting the synergy between Aβ‐dependent and LATE‐NC‐specific pathways in LATE‐NC pathogenesis. Three additional loci reached a pre‐specified suggestive p‐value threshold (p<1.0×10−6; CMTM7 [rs56284874G], RNF145 [rs111653954T], and CACNA2D3 [rs71303704C]). A previously reported FTLD‐TDP risk locus in TMEM106B (rs1990622A) showed a weaker positive association with LATE‐NC (meta‐analysis p = 9.6×10−4).ConclusionOur GWAS revealed LATE‐NC‐specific risk loci (SHANK2 and other suggestive loci). The unique genetic architecture of LATE‐NC further supports the distinction between LATE‐NC and FTLD‐TDP, and the AD‐independent effect of APOE ε4 on LATE‐NC highlights the pleiotropic role of APOE in neurodegeneration.

Alcoholic Hericium erinaceus mycelia extract induces SIRT-1/ERK-1/2 mediated autophagy to prevent accumulation and spreading of alpha-synuclein and amyloid-beta peptide on the A53T transgenic mice

Alpha-synuclein (α-syn) and amyloid-beta peptide (Aβ) accumulation cause neurodegenerative diseases. The accumulation of neurotoxins, like Aβ, tau, and α-syn is related to aging therefore studying aging mediated neurodegenerative disease is important. In this study, we used A53T tg mice in this mice behavioral and motor abnormalities could be promoted by Aβ and α-syn interaction, and we decided to prevent this interaction and their associated accumulation in the SN brain region in the A53T tg mice by Hericium erinaceus treatment. Three-month-old A53T mice were separated into three groups A53T, A53T+ low dose alcohol extracted mycelium (3.2 mg/30 g BW/day), and A53T+ high dose alcohol extracted mycelium (6.4 mg/30 g BW/day). Age-matched normal mice were used as a control. Our results confirmed that Hericium erinaceus mycelia extract prevented the formation of Aβ-mediated α-syn accumulation in the SN brain region of A53T tg mice by activating SIRT-1/ERK-1/2 mediated autophagy. We confirmed that SIRT-1/ERK-1/2 mediated autophagy via Hericium erinaceus treatment prevents Aβ and α-syn accumulation and regulates dopamine neuron survival. Our study makes significant contribution because we reported for the first time that Hericium erinaceus mycelia prevents the formation and accumulation of Aβ and α-syn in A53T tg mice by regulating SIRT-1/ERK-1/2 mediated autophagy.