Brain Aβ Research Articles

Expression of regional brain amyloid-β deposition with [18F]Flutemetamol in Centiloid scale -a multi-site study.

The Centiloid project helps calibrate the quantitative amyloid-β (Aβ) load into a unified Centiloid (CL) scale that allows data comparison across multi-site. How the smaller regional amyloid converted into CL has not been attempted. We first aimed to express regional Aβ deposition in CL using [18F]Flutemetamol and evaluate regional Aβ deposition in CL with that in standardized uptake value ratio (SUVr). Second, we aimed to determine the presence or absence of focal Aβ deposition by measuring regional CL in equivocal cases showing negative global CL. Following the Centiloid project pipeline, Level-1 replication, Level-2 calibration, and quality control were completed to generate corresponding Centiloid conversion equations to convert SUVr into Centiloid at regional levels. In equivocal cases, the regional CL was compared with visual inspection to evaluate regional Aβ positivity. 14 out of 16 regional conversions from [18F]Flutemetamol SUVr to Centiloid successfully passed the quality control, showing good reliability and relative variance, especially precuneus/posterior cingulate and prefrontal regions with good stability for Centiloid scaling. The absence of focal Aβ deposition could be detected by measuring regional CL, showing a high agreement rate with visual inspection. The regional Aβ positivity in the bilateral anterior cingulate cortex was most prevalent in equivocal cases. The expression of regional brain Aβ deposition in CL with [18F]Flutemetamol has been attempted in this study. Equivocal cases had focal Aβ deposition that can be detected by measuring regional CL.

The Compartmentalization of Amyloid-β in Idiopathic Normal Pressure Hydrocephalus Brain Biopsies.

Amyloid-β (Aβ) is one of the hallmark lesions of Alzheimer's disease (AD). During the disease process, Aβ undergoes biochemical changes, producing toxic Aβ variants, proposed to be detected within the neurons. Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive impairment, gait, and urinary symptoms in elderly, that can be reversed by a ventriculo-peritoneal shunt. Majority of iNPH subjects display different Aβ variants in their brain biopsies, obtained during shunting. To study the cellular compartmentalization of different Aβ variants in brain biopsies from iNPH subjects. We studied the cellular localization of different proteoforms of Aβ using antibodies towards different amino acid sequences or post-translational modifications of Aβ, including clones 4G8, 6F/3D, unmodified- (7H3D6), pyroglutamylated- (N3pE), phosphorylated-(1E4E11) Aβ and Aβ protein precursor (AβPP), in brain biopsies from 3 iNPH subjects, using immunohistochemistry and light microscopy (LM), light microscopy on semi-thin sections (LMst), and electron microscopy (EM). In LM all Aβ variants were detected. In LMst and EM, the Aβ 4G8, 6F/3D, and the pyroglutamylated Aβ were detected. The AβPP was visualized by all methods. The Aβ labelling was located extracellularly with no specific signal within the intracellular compartment, whereas the AβPP was seen both intra- and extracellularly. The Aβ markers displayed extracellular localization when visualized by three assessment techniques, reflecting the pathological extracellular accumulation of Aβ in the human brain. No intracellular Aβ pathology was seen. AβPP was visualized in intra- and extracellularly, which corresponds to the localization of the protein in the membranes of cells and organelles.

Association of Neurotrophic Factors at Midlife With In Vivo Measures of β-Amyloid and Tau Burden 15 Years Later in Dementia-Free Adults.

Neurotrophic factors (NTFs) play an important role in Alzheimer disease (AD) pathophysiology. Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are important NTFs. However, a direct link of BDNF and VEGF circulating levels with in vivo measures of amyloid-β (Aβ) and tau burden remains to be elucidated. We explored the relationship of BDNF and VEGF serum levels with future brain Aβ and tau pathology in a cohort of cognitively healthy, predominantly middle-aged adults and tested for possible effect modifications by sex and menopausal status. This cross-sectional analysis was conducted using data from the Framingham Heart Study (FHS), a community-based cohort study. The study sample included cognitively healthy participants from the FHS Offspring and Third-generation cohorts. BDNF and VEGF were measured in the third-generation cohort during examination cycles 2 (2005-2008) and 1 (2002-2005), respectively, and in the offspring cohort during examination cycle 7 (1998-2001). Participants underwent 11C-Pittsburgh compound B amyloid and 18F-Flortaucipir tau-PET imaging (2015-2021). Linear regression models were used to assess the relationship of serum BDNF and VEGF levels with regional tau and global Aβ, adjusting for potential confounders. Interactions with sex and menopausal status were additionally tested. The sample included 414 individuals (mean age = 41 ± 9 years; 51% female). Continuous measures of BDNF and VEGF were associated with tau signal in the rhinal region after adjustment for potential confounders (β = -0.15 ± 0.06, p = 0.018 and β = -0.19 ± 0.09, p = 0.043, respectively). High BDNF (≥32,450 pg/mL) and VEGF (≥488 pg/mL) levels were significantly related to lower rhinal tau (β = -0.27 ± 0.11, p = 0.016 and β = -0.40 ± 0.14, p = 0.004, respectively) and inferior temporal tau (β = -0.24 ± 0.11, p = 0.028 and β = -0.26 ± 0.13, p = 0.049, respectively). The BDNF-rhinal tau association was observed only among male individuals. Overall, BDNF and VEGF were not associated with global amyloid; however, high VEGF levels were associated with lower amyloid burden in postmenopausal women (β = -1.96 ± 0.70, p = 0.013, per 1 pg/mL). This study demonstrates a robust association between BDNF and VEGF serum levels with in vivo measures of tau almost 2 decades later. These findings add to mounting evidence from preclinical studies suggesting a role of NTFs as valuable blood biomarkers for AD risk prediction.

Suboptimal self-reported sleep efficiency and duration are associated with faster accumulation of brain amyloid beta in cognitively unimpaired older adults.

This study investigated whether self-reported sleep quality is associated with brain amyloid beta (Aβ) accumulation. Linear mixed effect model analyses were conducted for 189 cognitively unimpaired (CU) older adults (mean±standard deviation 74.0±6.2; 53.2% female), with baseline self-reported sleep data, and positron emission tomography-determined brain Aβ measured over a minimum of three time points (range 33.3-72.7 months). Analyses included random slopes and intercepts, interaction for apolipoprotein E (APOE) ε4 allele status, and time, adjusting for sex and baseline age. Sleep duration<6hours, in APOE ε4 carriers, and sleep efficiency<65%, in the whole sample and APOE ε4 non-carriers, is associated with faster accumulation of brain Aβ. These findings suggest a role for self-reported suboptimal sleep efficiency and duration in the accumulation of Alzheimer's disease (AD) neuropathology in CU individuals. Additionally, poor sleep efficiency represents a potential route via which individuals at lower genetic risk may progress to preclinical AD. In cognitively unimpaired older adults self-report sleep is associated with brain amyloid beta (Aβ) accumulation.Across sleep characteristics, this relationship differs by apolipoprotein E (APOE) genotype.Sleep duration<6hours is associated with faster brain Aβ accumulation in APOE ε4 carriers.Sleep efficiency< 65% is associated with faster brain Aβ accumulation in APOE ε4 non-carriers.Personalized sleep interventions should be studied for potential to slow Aβ accumulation.

Cognitive decline, Aβ pathology, and blood–brain barrier function in aged 5xFAD mice

BackgroundPatients with Alzheimer's disease (AD) develop blood–brain barrier dysfunction to varying degrees. How aging impacts Aβ pathology, blood–brain barrier function, and cognitive decline in AD remains largely unknown. In this study, we used 5xFAD mice to investigate changes in Aβ levels, barrier function, and cognitive decline over time.Methods5xFAD and wild-type (WT) mice were aged between 9.5 and 15.5 months and tested for spatial learning and reference memory with the Morris Water Maze (MWM). After behavior testing, mice were implanted with acute cranial windows and intravenously injected with fluorescent-labeled dextrans to assess their in vivo distribution in the brain by two-photon microscopy. Images were processed and segmented to obtain intravascular intensity, extravascular intensity, and vessel diameters as a measure of barrier integrity. Mice were sacrificed after in vivo imaging to isolate brain and plasma for measuring Aβ levels. The effect of age and genotype were evaluated for each assay using generalized or cumulative-linked logistic mixed-level modeling and model selection by Akaike Information Criterion (AICc). Pairwise comparisons were used to identify outcome differences between the two groups.Results5xFAD mice displayed spatial memory deficits compared to age-matched WT mice in the MWM assay, which worsened with age. Memory impairment was evident in 5xFAD mice by 2–threefold higher escape latencies, twofold greater cumulative distances until they reach the platform, and twice as frequent use of repetitive search strategies in the pool when compared with age-matched WT mice. Presence of the rd1 allele worsened MWM performance in 5xFAD mice at all ages but did not alter the rate of learning or probe trial outcomes. 9.5-month-old 15.5-month-old 5xFAD mice had twofold higher brain Aβ40 and Aβ42 levels (p < 0.001) and 2.5-fold higher (p = 0.007) plasma Aβ40 levels compared to 9.5-month-old 5xFAD mice. Image analysis showed that vessel diameters and intra- and extravascular dextran intensities were not significantly different in 9.5- and 15.5-month-old 5xFAD mice compared to age-matched WT mice.Conclusion5xFAD mice continue to develop spatial memory deficits and increased Aβ brain levels while aging. Given in vivo MP imaging limitations, further investigation with smaller molecular weight markers combined with advanced imaging techniques would be needed to reliably assess subtle differences in barrier integrity in aged mice.

Specific Binding of Alzheimer's Aβ Peptides to Extracellular Vesicles.

Alzheimer's disease (AD) is the fifth leading cause of death among adults aged 65 and older, yet the onset and progression of the disease is poorly understood. What is known is that the presence of amyloid, particularly polymerized Aβ42, defines when people are on the AD continuum. Interestingly, as AD progresses, less Aβ42 is detectable in the plasma, a phenomenon thought to result from Aβ becoming more aggregated in the brain and less Aβ42 and Aβ40 being transported from the brain to the plasma via the CSF. We propose that extracellular vesicles (EVs) play a role in this transport. EVs are found in bodily fluids such as blood, urine, and cerebrospinal fluid and carry diverse "cargos" of bioactive molecules (e.g., proteins, nucleic acids, lipids, metabolites) that dynamically reflect changes in the cells from which they are secreted. While Aβ42 and Aβ40 have been reported to be present in EVs, it is not known whether this interaction is specific for these peptides and thus whether amyloid-carrying EVs play a role in AD and/or serve as brain-specific biomarkers of the AD process. To determine if there is a specific interaction between Aβ and EVs, we used isothermal titration calorimetry (ITC) and discovered that Aβ42 and Aβ40 bind to EVs in a manner that is sequence specific, saturable, and endothermic. In addition, Aβ incubation with EVs overnight yielded larger amounts of bound Aβ peptide that was fibrillar in structure. These findings point to a specific amyloid-EV interaction, a potential role for EVs in the transport of amyloid from the brain to the blood, and a role for this amyloid pool in the AD process.

Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease.

Although glymphatic function is involved in Alzheimer's disease (AD), its potential for predicting the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood. Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS) in participants with AD dementia (n=47), mild cognitive impairment (MCI; n=137), and normal controls (n=235) from the Alzheimer's Disease Neuroimaging Initiative. ALPS index was significantly lower in AD dementia than in MCI or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy. Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD. The analysis along the perivascular space (ALPS) index is reduced in patients with Alzheimer's disease (AD) dementia, prodromal AD, and preclinical AD. Lower ALPS index predicted accelerated amyloid beta (Aβ) positron emission tomography (PET) burden and Aβ-positive transition. The decrease in the ALPS index occurs before cerebrospinal fluid Aβ42 reaches the positive threshold. ALPS index predicted brain atrophy, clinical progression, and cognitive decline. Aβ PET and brain atrophy mediated the link of ALPS index with cognitive decline.

Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs.

Alzheimer's disease is a complex multifactorial neurodegenerative disorder wherein age is a major risk factor. The appropriateness of the Hartley guinea pig (GP), which displays high sequence homologies of its amyloid-β (Aβ40 and Aβ42) peptides, Mdr1 and APP(amyloid precursor protein) and similarity in lipid handling to humans, was appraised among 9-40weeks old guinea pigs. Protein expression levels of P-gp (Abcb1) and Cyp46a1 (24(S)-hydroxylase) for Aβ40, and Aβ42 efflux and cholesterol metabolism, respectively, were decreased with age, whereas those for Lrp1 (low-density lipoprotein receptor related protein 1), Rage (receptor for advanced glycation endproducts) for Aβ efflux and influx, respectively, and Abca1 (the ATP binding cassette subfamily A member 1) for cholesterol efflux, were unchanged among the ages examined. There was a strong, negative correlation of the brain Aβ peptide concentrations and Abca1 protein expression levels with free cholesterol. The correlation of Aβ peptide concentrations with Cyp46a1 was, however, not significant, and concentrations of the 24(S)-hydroxycholesterol metabolite revealed a decreasing trend from 20weeks old toward 40weeks old guinea pigs. The composite data suggest a role for free cholesterol on brain Aβ accumulation. The decreases in P-gp and Lrp1 protein levels should further exacerbate the accumulation of Aβ peptides in guinea pig brain.

Sustained meningeal lymphatic vessel atrophy or expansion does not alter Alzheimer’s disease-related amyloid pathology

Discovery of meningeal lymphatic vessels (LVs) in the dura mater, also known as dural LVs (dLVs) that depend on vascular endothelial growth factor C expression, has raised interest in their possible involvement in Alzheimer’s disease (AD). Here we find that in the APdE9 and 5xFAD mouse models of AD, dural amyloid-β (Aβ) is confined to blood vessels and dLV morphology or function is not altered. The induction of sustained dLV atrophy or hyperplasia in the AD mice by blocking or overexpressing vascular endothelial growth factor C, impaired or improved, respectively, macromolecular cerebrospinal fluid (CSF) drainage to cervical lymph nodes. Yet, sustained manipulation of dLVs did not significantly alter the overall brain Aβ plaque load. Moreover, dLV atrophy did not alter the behavioral phenotypes of the AD mice, but it improved CSF-to-blood drainage. Our results indicate that sustained dLV manipulation does not affect Aβ deposition in the brain and that compensatory mechanisms promote CSF clearance.

Reducing brain Aβ burden ameliorates high-fat diet-induced fatty liver disease in APP/PS1 mice

High-fat diet (HFD)-induced fatty liver disease is a deteriorating risk factor for Alzheimer’s disease (AD). Mitigating fatty liver disease has been shown to attenuate AD-like pathology in animal models. However, it remains unclear whether enhancing Aβ clearance through immunotherapy would in turn attenuate HFD-induced fatty liver or whether its efficacy would be compromised by long-term exposure to HFD. Here, the therapeutic potentials of an anti-Aβ antibody, NP106, was investigated in APP/PS1 mice by HFD feeding for 44 weeks. The data demonstrate that NP106 treatment effectively reduced Aβ burden and pro-inflammatory cytokines in HFD-fed APP/PS1 mice and ameliorated HFD-aggravated cognitive impairments during the final 18 weeks of the study. The rejuvenating characteristics of microglia were evident in APP/PS1 mice with NP106 treatment, namely enhanced microglial Aβ phagocytosis and attenuated microglial lipid accumulation, which may explain the benefits of NP106. Surprisingly, NP106 also reduced HFD-induced hyperglycemia, fatty liver, liver fibrosis, and hepatic lipids, concomitant with modifications in the expressions of genes involved in hepatic lipogenesis and fatty acid oxidation. The data further reveal that brain Aβ burden and behavioral deficits were positively correlated with the severity of fatty liver disease and fasting serum glucose levels. In conclusion, our study shows for the first time that anti-Aβ immunotherapy using NP106, which alleviates AD-like disorders in APP/PS1 mice, ameliorates fatty liver disease. Minimizing AD-related pathology and symptoms may reduce the vicious interplay between central AD and peripheral fatty liver disease, thereby highlighting the importance of developing AD therapies from a systemic disease perspective.

Bile acid profile associated with CSF and PET biomarkers in Alzheimer’s disease

BackgroundRecent studies have shown that gut microbiota can affect the development of Alzheimer’s disease (AD) through various mechanisms. Bile acids (BAs), which are the final byproducts of cholesterol metabolism created through both the human body and gut microbiome, appear to be influenced by gut microbiota and may impact AD pathological characteristics such as the accumulation of tau and amyloid-β. We aimed to investigate the associations between various serum BAs and CSF biomarkers (including Aβ, total tau, and p-tau). Additionally, we sought to examine the longitudinal changes in brain Aβ and tau through PET imaging in relation to BAs profile.MethodsThe data of 828 subjects including 491 diagnosed with mild cognitive impairment (MCI), 119 patients diagnosed with AD, and 267 cognitively normal (CN) participants were obtained from ADNI. The baseline and longitudinal [18F] florbetapir and [18F] flortaucipir PET standard uptake value ratios (SUVR) measures were obtained to assess the accumulation of tau and Aβ. Moreover, baseline levels of serum BAs and CSF Aβ1–42, tau, and p-tau were used.ResultsAfter FDR correction we observed that five BAs level and relevant calculated ratios were associated with CSF p-tau and tau, three with CSF Aβ1–42. Furthermore, three BAs level and relevant calculated ratios were associated with the tau-PET rate of change, and two with the Aβ rate of change.ConclusionThe findings from our study suggest a correlation between altered profiles of BAs and CSF and imaging biomarkers associated with AD. These results provide supporting evidence for the link between the gut microbiome and the pathological features of AD.

MiR-3940-5p reduces amyloid β production via selectively targeting PSEN1.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid beta (Aβ) in brain. Mounting evidence has revealed critical roles of microRNAs (miRNAs) in AD pathogenesis; however, the miRNAs directly targeting presenilin1 (PSEN1), which encodes the catalytic core subunit of γ-secretase that limits the production of Aβ from amyloid precursor protein (APP), are extremely understudied. The present study aimed to identify miRNAs targeting PSEN1 and its effect on Aβ production. This study first predicted 5 candidate miRNAs that may target PSEN1,through websites such as TargetScan, miRDB, and miRwalk. Subsequently, the targeting specificity of the candidate miRNAs towards PS1 was validated using dual-luciferase reporter assays. To investigate the regulatory effect of miR-3940-5p on gene expression based on its targeting of PS1, miR-3940-5p mimics or inhibitors were transiently transfected into SH-SY5Y cells. Changes in PSEN1 transcription and translation in the tested cells were detected using RT-qPCR and Western Blot, respectively. Finally, to explore whether miR-3940-5p affects Aβ production, SH-SY5Y APPswe cells overexpressing the Swedish mutant type of APP were transiently transfected with miR-3940-5p mimics, and the expression level of Aβ was detected using ELISA. The results are as follows: The dual-luciferase reporter assays validated the targeting specificity of miR-3940-5p for PSEN1. Overexpression of miR-3940-5p significantly reduced the mRNA and protein levels of PSEN1 in SH-SY5Y cells. Conversely, inhibition of miR-3940-5p led to an increase in PSEN1 mRNA levels. Transfection of miR-3940-5p mimics into SH-SY5Y-APPswe cells resulted in a significant reduction in Aβ42 and Aβ40. Lentiviral-mediated overexpression of miR-3940-5p significantly decreased the expression of PSEN1 and did not significantly affect the expression of other predicted target genes. Furthermore, stable overexpression of miR-3940-5p in SH-SY5Y-APPswe cells mediated by lentivirus significantly reduced the expression of PSEN1 and the production of Aβ42 and Aβ40. Therefore, our study demonstrates for the first time the functional importance of miR-3940-5p in antagonizing Aβ production through specific and direct targeting of PSEN1.

Reduction of Amyloid-β Production without Inhibiting Secretase Activity by MS-275.

Brain amyloid-β (Aβ) governs the pathogenic process of Alzheimer's disease. Clinical trials to assess the disease-modifying effects of inhibitors or modulators of β- and γ-secretases have not shown clinical benefit and can cause serious adverse events. Previously, we found that the interleukin-like epithelial-to-mesenchymal transition inducer (ILEI, also known as FAM3C) negatively regulates the Aβ production through a decrease in Aβ immediate precursor, without the inhibition of β- and γ-secretase activity. Herein, we found that MS-275, a benzamide derivative that is known to inhibit histone deacetylases (HDACs), exhibits ILEI-like activity to reduce Aβ production independent of HDAC inhibition. Chronic MS-275 treatment decreased Aβ deposition in the cerebral cortex and hippocampus in an Alzheimer's disease mouse model. Overall, our results indicate that MS-275 is a potential therapeutic candidate for efficiently reducing brain Aβ accumulation.

Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests

With the emergence of Alzheimer’s disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. In this study, we evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio of phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry in the Swedish BioFINDER-2 cohort (n = 1,422) and the US Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) cohort (n = 337). Matched CSF samples were analyzed with clinically used and FDA-approved automated immunoassays for Aβ42/40 and p-tau181/Aβ42. The primary and secondary outcomes were detection of brain Aβ or tau pathology, respectively, using positron emission tomography (PET) imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying treatments. Plasma %p-tau217 was clinically equivalent to FDA-approved CSF tests in classifying Aβ PET status, with an area under the curve (AUC) for both between 0.95 and 0.97. Plasma %p-tau217 was generally superior to CSF tests in classification of tau-PET with AUCs of 0.95–0.98. In cognitively impaired subcohorts (BioFINDER-2: n = 720; Knight ADRC: n = 50), plasma %p-tau217 had an accuracy, a positive predictive value and a negative predictive value of 89–90% for Aβ PET and 87–88% for tau PET status, which was clinically equivalent to CSF tests, further improving to 95% using a two-cutoffs approach. Blood plasma %p-tau217 demonstrated performance that was clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. Use of high-performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD-specific treatments.

High-Fat Diets in Animal Models of Alzheimer's Disease: How Can Eating Too Much Fat Increase Alzheimer's Disease Risk?

High dietary intake of saturated fatty acids is a suspected risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). To decipher the causal link behind these associations, high-fat diets (HFD) have been repeatedly investigated in animal models. Preclinical studies allow full control over dietary composition, avoiding ethical concerns in clinical trials. The goal of the present article is to provide a narrative review of reports on HFD in animal models of AD. Eligibility criteria included mouse models of AD fed a HFD defined as > 35% of fat/weight and western diets containing > 1% cholesterol or > 15% sugar. MEDLINE and Embase databases were searched from 1946 to August 2022, and 32 preclinical studies were included in the review. HFD-induced obesity and metabolic disturbances such as insulin resistance and glucose intolerance have been replicated in most studies, but with methodological variability. Most studies have found an aggravating effect of HFD on brain Aβ pathology, whereas tau pathology has been much less studied, and results are more equivocal. While most reports show HFD-induced impairment on cognitive behavior, confounding factors may blur their interpretation. In summary, despite conflicting results, exposing rodents to diets highly enriched in saturated fat induces not only metabolic defects, but also cognitive impairment often accompanied by aggravated neuropathological markers, most notably Aβ burden. Although there are important variations between methods, particularly the lack of diet characterization, these studies collectively suggest that excessive intake of saturated fat should be avoided in order to lower the incidence of AD.

Exposure to Low-Intensity Blast Increases Clearance of Brain Amyloid Beta.

The long-term effects of exposure to blast overpressure are an important health concern in military personnel. Increase in amyloid beta (Aβ) has been documented after non-blast traumatic brain injury (TBI) and may contribute to neuropathology and an increased risk for Alzheimer's disease. We have shown that Aβ levels decrease following exposure to a low-intensity blast overpressure event. To further explore this observation, we examined the effects of a single 37 kPa (5.4 psi) blast exposure on brain Aβ levels, production, and clearance mechanisms in the acute (24 h) and delayed (28 days) phases post-blast exposure in an experimental rat model. Aβ and, notably, the highly neurotoxic detergent soluble Aβ42 form, was reduced at 24 h but not 28 days after blast exposure. This reduction was not associated with changes in the levels of Aβ oligomers, expression levels of amyloid precursor protein (APP), or increase in enzymes involved in the amyloidogenic cleavage of APP, the β- and ϒ-secretases BACE1 and presenilin-1, respectively. The levels of ADAM17 α-secretase (also known as tumor necrosis factor α-converting enzyme) decreased, concomitant with the reduction in brain Aβ. Additionally, significant increases in brain levels of the endothelial transporter, low-density related protein 1 (LRP1), and enhancement in co-localization of aquaporin-4 (AQP4) to perivascular astrocytic end-feet were observed 24 h after blast exposure. These findings suggest that exposure to low-intensity blast may enhance endothelial clearance of Aβ by LRP1-mediated transcytosis and alter AQP4-aided glymphatic clearance. Collectively, the data demonstrate that low-intensity blast alters enzymatic, transvascular, and perivascular clearance of Aβ.

Definition of a Threshold for the Plasma Aβ42/Aβ40 Ratio Measured by Single-Molecule Array to Predict the Amyloid Status of Individuals without Dementia.

Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) plaques and hyperphosphorylated tau in the brain. Aβ plaques precede cognitive impairments and can be detected through amyloid-positron emission tomography (PET) or in cerebrospinal fluid (CSF). Assessing the plasma Aβ42/Aβ40 ratio seems promising for non-invasive and cost-effective detection of brain Aβ accumulation. This approach involves some challenges, including the accuracy of blood-based biomarker measurements and the establishment of clear, standardized thresholds to categorize the risk of developing brain amyloid pathology. Plasma Aβ42/Aβ40 ratio was measured in 277 volunteers without dementia, 70 AD patients and 18 non-AD patients using single-molecule array. Patients (n = 88) and some volunteers (n = 66) were subject to evaluation of amyloid status by CSF Aβ quantification or PET analysis. Thresholds of plasma Aβ42/Aβ40 ratio were determined based on a Gaussian mixture model, a decision tree, and the Youden's index. The 0.0472 threshold, the one with the highest sensitivity, was retained for general population without dementia screening, and the 0.0450 threshold was retained for research and clinical trials recruitment, aiming to minimize the need for CSF or PET analyses to identify amyloid-positive individuals. These findings offer a promising step towards a cost-effective method for identifying individuals at risk of developing AD.

How Can We Use Mathematical Modeling of Amyloid-β in Alzheimer's Disease Research and Clinical Practices?

The accumulation of amyloid-β (Aβ) plaques in the brain is considered a hallmark of Alzheimer's disease (AD). Mathematical modeling, capable of predicting the motion and accumulation of Aβ, has obtained increasing interest as a potential alternative to aid the diagnosis of AD and predict disease prognosis. These mathematical models have provided insights into the pathogenesis and progression of AD that are difficult to obtain through experimental studies alone. Mathematical modeling can also simulate the effects of therapeutics on brain Aβ levels, thereby holding potential for drug efficacy simulation and the optimization of personalized treatment approaches. In this review, we provide an overview of the mathematical models that have been used to simulate brain levels of Aβ (oligomers, protofibrils, and/or plaques). We classify the models into five categories: the general ordinary differential equation models, the general partial differential equation models, the network models, the linear optimal ordinary differential equation models, and the modified partial differential equation models (i.e., Smoluchowski equation models). The assumptions, advantages and limitations of these models are discussed. Given the popularity of using the Smoluchowski equation models to simulate brain levels of Aβ, our review summarizes the history and major advancements in these models (e.g., their application to predict the onset of AD and their combined use with network models). This review is intended to bring mathematical modeling to the attention of more scientists and clinical researchers working on AD to promote cross-disciplinary research.

Huanshaodan regulates microglial glucose metabolism reprogramming to alleviate neuroinflammation in AD mice through mTOR/HIF-1α signaling pathway.

Abnormal glucose metabolism in microglial is closely associated with Alzheimer's disease (AD). Reprogramming of microglial glucose metabolism is centered on regulating the way in which microglial metabolize glucose to alter microglial function. Therefore, reprogramming microglial glucose metabolism is considered as a therapeutic strategy for AD. Huanshaodan (HSD) is a Chinese herbal compound which shows significant efficacy in treating AD, however, the precise mechanism by which HSD treats AD remains unclear. This study is aim to investigate whether HSD exerts anti-AD effects by regulating the metabolic reprogramming of microglial through the mTOR/HIF-1α signaling pathway. SAMP8 mice and BV2 cells were used to explore the alleviative effect of HSD on AD and the molecular mechanism in vivo and in vitro. The pharmacodynamic effects of HSD was evaluated by behavioral tests. The pathological deposition of Aβ in brain of mice was detected by immunohistochemistry. ELISA method was used to measure the activity of HK2 and the expression of PKM2, IL-6 and TNF-α in hippocampus and cortex tissues of mice. Meanwhile, proteins levels of p-mTOR, mTOR, HIF-1α, CD86, Arg1 and IL-1β were detected by Western-blot. LPS-induced BV2 cells were treated with HSD-containing serum. The analysis of the expression profiles of the CD86 and CD206 markers by flow cytometry allows us to distinguish the BV2 polarization. Glucose, lactic acid, ATP, IL-6 and TNF-α levels, as well as lactate dehydrogenase and pyruvate dehydrogenase activities were evaluated in the BV2. Western-blot analysis was employed to detect mTOR, p-mTOR, HIF-1α and IL-1β levels in BV2. And the mTOR agonist MHY1485 (MHY) was chosen to reverse validate. In this study, it is found that HSD improved cognitive impairment in SAMP8 mice and reduced Aβ deposition, suppressed the levels of glycolysis and neuroinflammation in mice. In LPS-induced BV2 cells, HSD also regulated glycolysis and neuroinflammation, and suppressed the mTOR/HIF-1α signaling pathway. More importantly, these effects were reversed by MHY. It is demonstrated that HSD regulated microglial glucose metabolism reprogramming by inhibiting the mTOR/HIF-1α signaling pathway, alleviated neuroinflammation, and exerted anti-AD effects. This study provided scientific evidence for the clinical application of HSD for treating AD.

Up-regulation of myelin-associated glycoprotein is associated with the ameliorating effect of omega-3 polyunsaturated fatty acids on Alzheimer's disease progression in APP-PS1 transgenic mice.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive behavioral and cognitive impairments. Despite growing evidence of the neuroprotective action of omega-3 polyunsaturated fatty acids (PUFAs), the effects and mechanism of omega-3 PUFAs on AD control are yet to be clarified. By crossing male heterozygous fat-1 mice with female APP/PS1 mice, we assessed whether elevated tissue omega-3 PUFA levels could alleviate AD progression and their underlying mechanism among the offspring WT, APP/PS1 and APP/PS1 × fat-1 groups at various stages. We found that the fat-1 transgene significantly increased brain omega-3 PUFA and docosahexaenoic acid (DHA) levels, and cognitive deficits together with brain Aβ-40 and Aβ-42 levels in 6-month-old APP/PS1 × fat-1 mice were significantly lower than those in APP/PS1 mice. Subsequently, the tandem mass tag (TMT) method revealed the elevated expression of cortex and hippocampus myelin-associated glycoprotein (MAG) in APP/PS1 × fat-1 mice at 2-6 months. Furthermore, GO and KEGG pathway enrichment analysis suggested that the MAG-related myelin sheath pathway and its interaction with AD were regulated by omega-3 PUFAs. Moreover, subsequent western blot assays showed that both increased endogenous omega-3 levels and in vitro supplemented DHA up-regulated MAG expression, and the AD-protective effects of DHA on LPS-induced BV2 cells were significantly weakened when MAG was inhibited by si-RNA transfection. In summary, our study suggested that omega-3 PUFAs might protect against AD by up-regulating MAG expression.