Alzheimer's Amyloid Research Articles

Associations of cortical SPP1 and ITGAX with cognition and common neuropathologies in older adults.

The secreted phosphoprotein 1 (SPP1) gene expressed by CD11c+ cells is known to be associated with microglia activation and neuroinflammatory diseases. As most studies rely on mouse models, we investigated these genes and proteins in the cortical brain tissue of older adults and their role in Alzheimer's disease (AD) and related disorders. We leveraged protein measurements, single-nuclei, and RNASeq data from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) of over 1200 samples for association analysis. Expression ofSPP1and its encoded protein osteopontin were associated with faster cognitive decline and greater odds of common neuropathologies. At single-cell resolution, integrin subunit alpha X (ITGAX) was highly expressed in microglia, where specific subpopulations were associated with AD and cerebral amyloid angiopathy. The study provides evidence of SPP1andITGAXassociation with cognitive decline and common neuropathologies identifying a microglial subset associated with disease.

Beneficial effects of physical exercise and an orally active mGluR2/3 antagonist pro-drug on neurogenesis and behavior in an Alzheimer's amyloidosis model.

Modulation of physical activity represents an important intervention that may delay, slow, or prevent mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD). One mechanism proposed to underlie the beneficial effect of physical exercise (PE) involves the apparent stimulation of adult hippocampal neurogenesis (AHN). BCI-838 is a pro-drug whose active metabolite BCI-632 is a negative allosteric modulator at group II metabotropic glutamate receptors (mGluR2/3). We previously demonstrated that administration of BCI-838 to a mouse model of brain accumulation of oligomeric AβE22Q (APP E693Q = "Dutch APP") reduced learning behavior impairment and anxiety, both of which are associated with the phenotype of Dutch APP mice. 3-month-old mice were administered BCI-838 and/or physical exercise for 1 month and then tested in novel object recognition, neurogenesis, and RNAseq. Here we show that (i) administration of BCI-838 and a combination of BCI-838 and PE enhanced AHN in a 4-month old mouse model of AD amyloid pathology (APP KM670/671NL /PSEN1 Δexon9= APP/PS1), (ii) administration of BCI-838 alone or with PE led to stimulation of AHN and improvement in recognition memory, (iii) the hippocampal dentate gyrus transcriptome of APP/PS1 mice following BCI-838 treatment showed up-regulation of brain-derived neurotrophic factor (BDNF), PIK3C2A of the PI3K-mTOR pathway, and metabotropic glutamate receptors, and down-regulation of EIF5A involved in modulation of mTOR activity by ketamine, and (iv) validation by qPCR of an association between increased BDNF levels and BCI-838 treatment. Our study points to BCI-838 as a safe and orally active compound capable of mimicking the beneficial effect of PE on AHN and recognition memory in a mouse model of AD amyloid pathology.

Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk

The APOE 2/3/4 polymorphism is the greatest genetic risk factor for Alzheimer’s disease (AD). This polymorphism is also associated with variation in plasma ApoE level; while APOE*4 lowers, APOE*2 increases ApoE level. Lower plasma ApoE level has also been suggested to be a risk factor for incident dementia. To our knowledge, no large genome-wide association study (GWAS) has been reported on plasma ApoE level. This study aimed to identify new genetic variants affecting plasma ApoE level as well as to test if baseline ApoE level is associated with cognitive function and incident dementia in a longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Baseline plasma ApoE concentration was measured in 3031 participants (95.4% European Americans (EAs)). GWAS analysis was performed on 2580 self-identified EAs where both genotype and plasma ApoE data were available. Lower ApoE concentration was associated with worse cognitive function, but not with incident dementia. As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (P for trend = 4.8E-75). In addition to confirming the expected and opposite associations of APOE*2 (P = 4.73E-79) and APOE*4 (P = 8.73E-12) with ApoE level, GWAS analysis revealed nine additional independent signals in the APOE region, and together they explained about 22% of the variance in plasma ApoE level. We also identified seven new loci on chromosomes 1, 4, 5, 7, 11, 12 and 20 (P range = 5.49E-08 to 5.36E-10) that explained about 9% of the variance in ApoE level. Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with AD risk and amyloid deposition in the brain, indicating that genetically determined ApoE level variation may be a risk factor for developing AD. These results improve our understanding of the genetic determinants of plasma ApoE level and their potential value in affecting AD risk.

Amyloid pathology reduces ELP3 expression and tRNA modifications leading to impaired proteostasis

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by accumulation of β-amyloid aggregates and loss of proteostasis. Transfer RNA (tRNA) modifications play a crucial role in maintaining proteostasis, but their impact in AD remains unclear. Here, we report that expression of the tRNA modifying enzyme ELP3 is reduced in the brain of AD patients and amyloid mouse models and negatively correlates with amyloid plaque mean density. We further show that SH-SY5Y neuronal cells carrying the amyloidogenic Swedish familial AD mutation (SH-SWE) display reduced ELP3 levels, tRNA hypomodifications and proteostasis impairments when compared to cells not carrying the mutation (SH-WT). Additionally, exposing SH-WT cells to the secretome of SH-SWE cells led to reduced ELP3 expression, wobble uridine tRNA hypomodification, and increased protein aggregation. Importantly, correcting tRNA deficits due to ELP3 reduction reverted proteostasis impairments. These findings suggest that amyloid pathology dysregulates proteostasis by reducing ELP3 expression and tRNA modification levels, and that targeting tRNA modifications may be a potential therapeutic avenue to restore neuronal proteostasis in AD and preserve neuronal function.

Associations of Midlife Lifestyle and Health Factors with Long-Term Changes inBlood-Based Biomarkers of Alzheimer's Disease and Neurodegeneration.

Pathological biomarkers of Alzheimer's disease (AD) and other dementias can change decades before clinical symptoms. Lifestyle and health factors might be relevant modifiable risk factors for dementia. Many previous studies have been focusing on associations of lifestyle and health-related factors with clinical outcomes later in life. We aimed to determine to what extent midlife factors of lifestyle, inflammation, vascular, and metabolic health were associated with long-term changes in blood-based biomarkers of AD (amyloid beta (Aβ)) and neurodegeneration (neurofilament light chain (NfL); total tau(TTau)). In 1,529 Beaver Dam Offspring Study (BOSS) participants (mean age 49 years, standard deviation (SD) = 9;54% were women), we applied mixed-effects models with baseline risk factors as determinants and 10-year serum biomarker change as outcomes. We found that education and inflammatory markers were associated with levels and/or change over time across all three markers of AD and neurodegeneration in the blood. There were baseline associations of measures of cardiovascular health with lower Aβ42/Aβ40. TTau changed little over time and was higher in individuals with diabetes. Individuals with lower risk in a number of cardiovascular and metabolic risk factors, including diabetes, hypertension, and atherosclerosis had slower accumulation of neurodegeneration over time, as determined by NfL levels. Various lifestyle and health factors, including education and inflammation, were associated with longitudinal changes of neurodegenerative and AD biomarker levels in midlife. If confirmed, these findings could have important implications for developing early lifestyle and health interventions that could potentially slow processes of neurodegeneration and AD.

Aquaporin-4 Mediated Aggregation of Alzheimer's Amyloid β-Peptide.

Clearance of Alzheimer's amyloid oligomers from the brain is crucial for preventing cell toxicity. Dementia complications arise as a result of apoptosis, which is caused by peptide plaques on the lipid surface of cells. Here, we employed all-atom and coarse-grained molecular dynamics simulations to investigate the aggregation of amyloid peptides at the lipid surface and the role of aquaporin-4 (AQP4) in facilitating peptide clearance from astrocytes. The network of protein-protein interactions through text mining revealed that the expression of AQP4 and amyloid aggregation were strongly correlated. It has also been revealed that the role of aquaporins in the etiology of Alzheimer's disease involves several interconnected proteins and pathways. The nature of aggregation at the surface of the 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer was revealed by the interaction of amyloid oligomers. The membrane-bound pore region of AQP4 interacts with the peptide and slows its aggregation. This interaction maintains the helical content of the peptide while lowering its toxicity at the lipid surface. The hydrophobicity of the peptide also decreased because of these interactions, which may help in the removal of the peptide from astrocytes. Long-term coarse-grained MD simulations demonstrated different features of oligomer aggregation at the surface and strong oligomer attraction to AQP4, which inhibited aggregation. Additionally, the water dynamics of aquaporins demonstrate how the selectivity filter is broken to disrupt water flow. Our findings also provide insight into the physiological alterations in brain tissue associated with Alzheimer's disease, including water retention and increased water flow in the CSF. Furthermore, in vitro thioflavin fluorescence spectroscopy revealed a slower aggregation of the peptide in the presence of AQP4.

Tau as a diagnostic instrument in clinical trials to predict amyloid in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the presence of both amyloid and tau pathology. In vivo diagnosis can be made with amyloid and tau positron emission tomography (PET) imaging. Emergent evidence supports that amyloid and tau accumulation are associated and that amyloid accumulation may precede that of tau. This report further investigates the relationship between amyloid and tau to assess whether elevated cortical tau can predict elevated amyloid in participants with early symptomatic AD. Florbetapir F18 and flortaucipir F18 uptake were evaluated from baseline PET scans collected in three multi-center studies with cognitively impaired participants, including A05 (N = 306; NCT02016560), TB (N = 310; TRAILBLAZER-ALZ; NCT03367403), and TB2 (N = 1165; TRAILBLAZER-ALZ 2; NCT04437511). Images were assessed using visual and quantitative approaches to establish amyloid (A+) and tau (T+) positivity, as well as a combination method (tauVQ) to establish T+. Associations between global amyloid and tau were evaluated with positive and negative predictive values (PPV, NPV) and likelihood ratios (LR+, LR-). Predictive values within subgroups according to ethnicity, race, cognitive score, age, and sex were also evaluated. The relationship between regional tau (four target and two reference regions were tested) and global amyloid was investigated in A05 participant scans using receiver-operating characteristic (ROC) curves. PPV for amyloid positivity was ≥93% for all three trials using various A+ and T+ definitions, including visual, quantitative, and combination methods. Population characteristics did not have an impact on A+ predictability. Regional analyses (early tau (Eτ) volume of interest (VOI), temporal, parietal, frontal) revealed significant area under the ROC curve in Eτ VOI compared to frontal region, regardless of reference region and consistent among visual and quantitative A+ definitions (p < 0.001). These findings suggest that a positive tau PET scan is associated (≥93%) with amyloid positivity in individuals with early symptomatic AD, with the potential benefits of reducing clinical trial and health care expenses, radiation exposure, and participant time. Positron emission tomography (PET) evaluates candidates for Alzheimer's disease (AD) research. A positive tau PET scan is associated (≥93%) with amyloid positivity.A positive amyloid PET is not necessarily associated with tau positivity.Tau PET could be the sole diagnostic tool to confirm candidates for AD trials.

APOE Peripheral and Brain Impact: APOE4 Carriers Accelerate Their Alzheimer Continuum and Have a High Risk of Suicide in PM2.5 Polluted Cities

This Review emphasizes the impact of APOE4—the most significant genetic risk factor for Alzheimer’s disease (AD)—on peripheral and neural effects starting in childhood. We discuss major mechanistic players associated with the APOE alleles’ effects in humans to understand their impact from conception through all life stages and the importance of detrimental, synergistic environmental exposures. APOE4 influences AD pathogenesis, and exposure to fine particulate matter (PM2.5), manufactured nanoparticles (NPs), and ultrafine particles (UFPs) associated with combustion and friction processes appear to be major contributors to cerebrovascular dysfunction, neuroinflammation, and oxidative stress. In the context of outdoor and indoor PM pollution burden—as well as Fe, Ti, and Al alloys; Hg, Cu, Ca, Sn, and Si UFPs/NPs—in placenta and fetal brain tissues, urban APOE3 and APOE4 carriers are developing AD biological disease hallmarks (hyperphosphorylated-tau (P-tau) and amyloid beta 42 plaques (Aβ42)). Strikingly, for Metropolitan Mexico City (MMC) young residents ≤ 40 y, APOE4 carriers have 4.92 times higher suicide odds and 23.6 times higher odds of reaching Braak NFT V stage versus APOE4 non-carriers. The National Institute on Aging and Alzheimer’s Association (NIA-AA) framework could serve to test the hypothesis that UFPs and NPs are key players for oxidative stress, neuroinflammation, protein aggregation and misfolding, faulty complex protein quality control, and early damage to cell membranes and organelles of neural and vascular cells. Noninvasive biomarkers indicative of the P-tau and Aβ42 abnormal protein deposits are needed across the disease continuum starting in childhood. Among the 21.8 million MMC residents, we have potentially 4 million APOE4 carriers at accelerated AD progression. These APOE4 individuals are prime candidates for early neuroprotective interventional trials. APOE4 is key in the development of AD evolving from childhood in highly polluted urban centers dominated by anthropogenic and industrial sources of pollution. APOE4 subjects are at higher early risk of AD development, and neuroprotection ought to be implemented. Effective reductions of PM2.5, UFP, and NP emissions from all sources are urgently needed. Alzheimer’s Disease prevention ought to be at the core of the public health response and physicians-scientist minority research be supported.

Banks of the Superior Temporal Sulcus in Alzheimer's Disease: A Pilot Quantitative Susceptibility Mapping Study.

Brain iron homeostasis is disrupted in neurodegeneration and areas of iron overload partially overlap with regions of amyloid and tau burden in Alzheimer's disease (AD). Previous studies demonstrated alterations in brain iron accumulation in AD using quantitative susceptibility mapping (QSM). Here, we investigate brain alterations of QSM values in AD and non-AD patients as compared to healthy controls (HC) in the superior temporal sulcus and its banks (BANKSSTS), one of the top AD-affected regions. Thirty-four patients who underwent brain MRI including a multi-echo gradient-echo sequence were subdivided into AD (n = 19) and non-AD (n = 15) groups according to their clinical profile, CSF (Aβ42/40) and/or amyloid-PET status. Ten HC were also included. QSM values were extracted from left and right BANKSSTS and compared among groups. Correlation and binomial regression analyses between QSM values and CSF-AD biomarkers were conducted. QSM in left BANKSSTS was significantly different among groups (p = 0.003, H = 11.40), being higher in AD. QSM values in left BANKSSTS were correlated with Aβ42 (rho -0.55, p = 0.005), Aβ42/40 (rho -0.66, p < 0.001), pTau (rho 0.63, p < 0.001), tTau (rho 0.56, p = 0.005), tTau/Aβ42 (rho 0.68, p < 0.001) and pTau/Aβ42 (rho 0.71, p < 0.001). No correlations between QSM values and amyloid-PET SUVR in the left BANKSSTS were found. QSM values in left BANKSSTS showed good accuracy in discriminating AD (AUC = 0.80, CI95% [0.66-0.93]). Higher QSM values were independent predictors of Aβ42 (B = 0.63, p = 0.032), Aβ42/40 (B = 0.81, p = 0.028), pTau (B = 0.96, p = 0.046), tTau (B = 0.55, p = 0.027), and tTau/Aβ42 (B = 1.13, p = 0.042) positivity. Our preliminary data support the potential role of increased QSM values in the left BANKSSTS as an auxiliary imaging biomarker in AD diagnosis.

Amyloid-β is a cytokine.

The role of amyloid-β (Aβ) peptide in human physiology and pathology remains an unresolved subject of study; Aβ's role in Alzheimer's disease (AD) is particularly controversial. However, before we can more fully appreciate Aβ's role in AD, an understanding of its normal physiological role(s) must first be attained. This perspective appraises the current literature and concludes that Aβ is a cytokine. This conclusion was arrived at based on a comprehensive listing of 30 characteristic defining structural and functional properties of cytokines followed by a literature precedence-based demonstration that Aβ possesses all 30 properties; this categorization of cytokine characteristics enabled an organized comparison of cytokines and Aβ, thereby providing systematic justification for classifying Aβ as a cytokine. The conclusion that Aβ is a cytokine enables the merger of two leading hypotheses of AD (amyloid hypothesis and neuroinflammation) into a single process.

Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease.

A hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. We conducted a CSF proteome-wide analysis among participants of varying AT pathology (n=137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. We identified 61 proteins significantly associated with the AT category (P<5.46×10-5 ) and 636 significant protein-biomarker associations (P<6.07×10-6 ). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n=717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. These results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. Cerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing. Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins. Key glucose/carbon metabolism protein associations independently replicated. CSF proteome outperformed other omics data in predicting amyloid/tau positivity. CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.

Predictive network analysis identifies JMJD6 and other potential key drivers in Alzheimer’s disease

Despite decades of genetic studies on late-onset Alzheimer’s disease, the underlying molecular mechanisms remain unclear. To better comprehend its complex etiology, we use an integrative approach to build robust predictive (causal) network models using two large human multi-omics datasets. We delineate bulk-tissue gene expression into single cell-type gene expression and integrate clinical and pathologic traits, single nucleotide variation, and deconvoluted gene expression for the construction of cell type-specific predictive network models. Here, we focus on neuron-specific network models and prioritize 19 predicted key drivers modulating Alzheimer’s pathology, which we then validate by knockdown in human induced pluripotent stem cell-derived neurons. We find that neuronal knockdown of 10 of the 19 targets significantly modulates levels of amyloid-beta and/or phosphorylated tau peptides, most notably JMJD6. We also confirm our network structure by RNA sequencing in the neurons following knockdown of each of the 10 targets, which additionally predicts that they are upstream regulators of REST and VGF. Our work thus identifies robust neuronal key drivers of the Alzheimer’s-associated network state which may represent therapeutic targets with relevance to both amyloid and tau pathology in Alzheimer’s disease.

FDA-approved carbonic anhydrase inhibitors reduce amyloid β pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness.

Cerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies. Based on the success of our previous in vitro studies, we tested for the first time in a model of AD and cerebral amyloid angiopathy (CAA), the carbonic anhydrase inhibitors (CAIs) methazolamide and acetazolamide, Food and Drug Administration-approved against glaucoma and high-altitude sickness. Both CAIs reduced cerebral, vascular, and glial amyloid beta (Aβ) accumulation and caspase activation, diminished gliosis, and ameliorated cognition in TgSwDI mice. The CAIs also improved microvascular fitness and induced protective glial pro-clearance pathways, resulting in the reduction of Aβ deposition. Notably, we unveiled that the mitochondrial carbonic anhydrase-VB (CA-VB) is upregulated in TgSwDI brains, CAA and AD+CAA human subjects, and in endothelial cells upon Aβ treatment. Strikingly, CA-VB silencing specifically reduces Aβ-mediated endothelial apoptosis. This work substantiates the potential application of CAIs in clinical trials for AD and CAA.

Brain Amyloid in Sporadic Young Onset Alzheimer's Disease.

Controversy exists as to the role of the amyloid-β (Aβ) peptide in the pathophysiology of Alzheimer's disease (AD). To clarify the effect of age on Aβ deposition in sporadic AD by exploring the degree of amyloid burden in patients with sporadic young onset AD (YOAD). Patients were diagnosed with YOAD with dementia starting before the age of 65 years (N = 42; males = 20, females = 22). A cross-sectional analysis of amyloid binding using positron emission tomography (PET) imaging was performed using the C-Pittsburgh Compound B (PiB). The global standardized uptake value ratios (gSUVR) were examined using the Wilcoxon two-sample test, as were the cognitive scores between disease and healthy control populations. Differences in PiB retention in different anatomical areas were compared using the Kruskal-Wallis test. The contrast in APOE genotyping between groups was calculated with Fisher's Exact Test. Women had a median gSUVR = 2.68±0.73 and 73% had at least one APOE ɛ4 allele. Men had gSUVR = 2.37±0.54, with 80% having at least one APOE ɛ4 allele. The gSUVRs were significantly higher than the control populations for men and women and had significantly greater frequency of APOE ɛ4. Men and women analyzed together had significantly greater amyloid burden and APOE ɛ4 allele frequencies than controls, but no differences existed between them in gSUVR nor in the anatomical distribution of amyloid uptake. Men and women with YOAD have greater amyloid uptake than controls and have more APOE ɛ4 alleles. Our findings suggest that the Aβ peptide is operational in young onset dementia and driven by the APOE ɛ4 allele.

Moving Beyond Amyloid in Alzheimer's Therapeutics

Moving Beyond Amyloid in Alzheimer's Therapeutics

Brain p3‐Alcβ peptide restores neuronal viability impaired by Alzheimer's amyloid β‐peptide

We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3‐Alcβ37 is generated from the neuronal protein alcadein β through cleavage of γ‐secretase, similar to the generation of amyloid β (Aβ) derived from Aβ‐protein precursor/APP. Neurotoxicity by Aβ oligomers (Aβo) is the prime cause prior to the loss of brain function in AD. We found that p3‐Alcβ37 and its shorter peptide p3‐Alcβ9‐19 enhanced the mitochondrial activity of neurons and protected neurons against Aβo‐induced toxicity. This is due to the suppression of the Aβo‐mediated excessive Ca2+ influx into neurons by p3‐Alcβ. Successful transfer of p3‐Alcβ9‐19 into the brain following peripheral administration improved the mitochondrial viability in the brain of AD mice model, in which the mitochondrial activity is attenuated by increasing the neurotoxic human Aβ42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased Aβ and reduced p3‐Alcβ37 levels, the administration of p3‐Alcβ9‐19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD.

Iron response elements (IREs)-mRNA of Alzheimer's amyloid precursor protein binding to iron regulatory protein (IRP1): a combined molecular docking and spectroscopic approach

The interaction between the stem-loop structure of the Alzheimer's amyloid precursor protein IRE mRNA and iron regulatory protein was examined by employing molecular docking and multi-spectroscopic techniques. A detailed molecular docking analysis of APP IRE mRNA∙IRP1 reveals that 11 residues are involved in hydrogen bonding as the main driving force for the interaction. Fluorescence binding results revealed a strong interaction between APP IRE mRNA and IRP1 with a binding affinity and an average binding sites of 31.3 × 106 M−1 and 1.0, respectively. Addition of Fe2+(anaerobic) showed a decreased (3.3-fold) binding affinity of APP mRNA∙IRP1. Further, thermodynamic parameters of APP mRNA∙IRP1 interactions were an enthalpy-driven and entropy-favored event, with a large negative ΔH (–25.7 ± 2.5 kJ/mol) and a positive ΔS (65.0 ± 3.7 J/mol·K). A negative ΔH value for the complex formation suggested the contribution of hydrogen bonds and van der Waals forces. The addition of iron increased the enthalpic contribution by 38% and decreased the entropic influence by 97%. Furthermore, the stopped-flow kinetics of APP IRE mRNA∙IRP1 also confirmed the complex formation, having the rate of association (kon) and the rate of dissociation (koff) as 341 μM−1 s−1, and 11 s−1, respectively. The addition of Fe2+ has decreased the rate of association (kon) by ~ three-fold, whereas the rate of dissociation (koff) has increased by ~ two-fold. The activation energy for APP mRNA∙IRP1 complex was 52.5 ± 2.1 kJ/mol. The addition of Fe2+ changed appreciably the activation energy for the binding of APP mRNA with IRP1. Moreover, circular dichroism spectroscopy has confirmed further the APP mRNA∙IRP1 complex formation and IRP1 secondary structure change with the addition of APP mRNA. In the interaction between APP mRNA and IRP1, iron promotes structural changes in the APP IRE mRNA∙IRP1 complexes by changing the number of hydrogen bonds and promoting a conformational change in the IRP1 structure when it is bound to the APP IRE mRNA. It further illustrates how IRE stem-loop structure influences selectively the thermodynamics and kinetics of these protein-RNA interactions.

Characteristics of Subjective Cognitive Decline Associated with Alzheimer's Disease Amyloid Pathology: Findings from The CABLE Study.

Subjective cognitive decline (SCD) is considered as a preclinical hallmark of Alzheimer's disease (AD). However, the characteristics of SCD associated with amyloid pathology remain unclear. We aimed to explore the associations between SCD characteristics with amyloid pathology. Using logistic regression analyses, we analyzed the associations between cerebrospinal fluid (CSF) amyloid pathology with AD risk factors, SCD-specific characteristics (onset of SCD within the last five years, age at onset ≥60 years, feelings of worse performance, informant confirmation of complaints, worries, other domains of cognition complaints), as well as subthreshold depressive and anxiety symptoms among individuals with SCD. A total of 535 SCD individuals with available CSF Aβ42 information from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study (mean age of 63.5 years, range 40 to 88 years; 47.10% female) were enrolled. The characteristics of informant confirmation of complaints (OR, 95% CI = 2.00, 1.19-3.36), subthreshold depressive symptoms (OR, 95% CI = 2.31, 1.05-5.09), and subthreshold anxiety symptoms (OR, 95% CI = 2.22, 1.09-4.51) were found to be significantly associated with pathological amyloid in multivariate analyses when adjusting for age, sex, education, and APOE ɛ4. Besides, age and females were observed risks for amyloid pathology in subscale analyses. Nonetheless, we did not find any associations of other SCD-specific characteristics with amyloid pathology in this study. Our study suggested that informant confirmed complaints and subthreshold psychiatric symptoms might be critical for discriminating AD-related SCD from non-AD related SCD.

CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease

Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer’s disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman’s ρ = 0.69) than Aβ42/Aβ40 (ρ = −0.42, P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD.

Alzheimer's disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression.

The synapse has consistently been considered a vulnerable and critical target within Alzheimer's disease, and synapse loss is, to date, one of the main biological correlates of cognitive decline within Alzheimer's disease. This occurs prior to neuronal loss with ample evidence that synaptic dysfunction precedes this, in support of the idea that synaptic failure is a crucial stage within disease pathogenesis. The two main pathological hallmarks of Alzheimer's disease, abnormal aggregates of amyloid or tau proteins, have had demonstrable effects on synaptic physiology in animal and cellular models of Alzheimer's disease. There is also growing evidence that these two proteins may have a synergistic effect on neurophysiological dysfunction. Here, we review some of the main findings of synaptic alterations in Alzheimer's disease, and what we know from Alzheimer's disease animal and cellular models. First, we briefly summarize some of the human evidence to suggest that synapses are altered, including how this relates to network activity. Subsequently, animal and cellular models of Alzheimer's disease are considered, highlighting mouse models of amyloid and tau pathology and the role these proteins may play in synaptic dysfunction, either in isolation or examining how the two pathologies may interact in dysfunction. This specifically focuses on neurophysiological function and dysfunction observed within these animal models, typically measured using electrophysiology or calcium imaging. Following synaptic dysfunction and loss, it would be impossible to imagine that this would not alter oscillatory activity within the brain. Therefore, this review also discusses how this may underpin some of the aberrant oscillatory patterns seen in animal models of Alzheimer's disease and human patients. Finally, an overview of some key directions and considerations in the field of synaptic dysfunction in Alzheimer's disease is covered. This includes current therapeutics that are targeted specifically at synaptic dysfunction, but also methods that modulate activity to rescue aberrant oscillatory patterns. Other important future avenues of note in this field include the role of non-neuronal cell types such as astrocytes and microglia, and mechanisms of dysfunction independent of amyloid and tau in Alzheimer's disease. The synapse will certainly continue to be an important target within Alzheimer's disease for the foreseeable future.