Aβ Levels Research Articles

Associations of sleep duration and daytime sleepiness with plasma amyloid beta and cognitive performance in cognitively unimpaired, middle-aged and older African Americans.

Given the established racial disparities in both sleep health and dementia risk for African American populations, we assess cross-sectional and longitudinal associations of self-report sleep duration (SRSD) and daytime sleepiness with plasma amyloid beta (Aβ) and cognition in an African American (AA) cohort. In a cognitively unimpaired sample drawn from the African Americans Fighting Alzheimer's in Midlife (AA-FAiM) study, data on SRSD, Epworth Sleepiness Scale, demographics, and cognitive performance were analyzed. Aβ40, Aβ42, and the Aβ42/40 ratio were quantified from plasma samples. Cross-sectional analyses explored associations between baseline predictors and outcome measures. Linear mixed-effect regression models estimated associations of SRSD and daytime sleepiness with plasma Aβ and cognitive performance levels and change over time. One hundred and forty-seven participants comprised the cross-sectional sample. Baseline age was 63.2 ± 8.51 years. 69.6% self-identified as female. SRSD was 6.4 ± 1.1 hours and 22.4% reported excessive daytime sleepiness. The longitudinal dataset included 57 participants. In fully adjusted models, neither SRSD nor daytime sleepiness is associated with cross-sectional or longitudinal Aβ. Associations with level and trajectory of cognitive test performance varied by measure of sleep health. SRSD was below National Sleep Foundation recommendations and daytime sleepiness was prevalent in this cohort. In the absence of observed associations with plasma Aβ, poorer self-reported sleep health broadly predicted poorer cognitive function but not accelerated decline. Future research is necessary to understand and address modifiable sleep mechanisms as they relate to cognitive aging in AA at disproportionate risk for dementia. Not applicable.

Changes in Multiparametric Magnetic Resonance Imaging and Plasma Amyloid-Beta Protein in Subjective Cognitive Decline.

The association between plasma amyloid-beta protein (Aβ) and subjective cognitive decline (SCD) remains controversial. We aimed to explore the correlation between neuroimaging findings, plasma Aβ, and neuropsychological scales using data from 53 SCD patients and 46 age- and sex-matched healthy controls (HCs). Magnetic resonance imaging (MRI) was used to obtain neuroimaging data for a whole-brain voxel-based morphometry analysis and cortical functional network topological features. The SCD group had slightly lower Montreal Cognitive Assessment (MoCA) scores than the HC group. The Aβ42 levels were significantly higher in the SCD group than in the HC group (p < 0.05). The SCD patients demonstrated reduced volumes in the left hippocampus, right rectal gyrus (REC.R), and right precentral gyrus (PreCG.R); an increased percentage fluctuation in the left thalamus (PerAF); and lower average small-world coefficient (aSigma) and average global efficiency (aEg) values. Correlation analyses with Aβ and neuropsychological scales revealed significant positive correlations between the volumes of the HIP.L, REC.R, PreCG.R, and MoCA scores. The HIP.L volume and Aβ42 were negatively correlated, as were the REC.R volume and Aβ42/40. PerAF and aSigma were negatively and positively correlated with the MoCA scores, respectively. The aEg was positively correlated with Aβ42/40. SCD patients may exhibit alterations in plasma biomarkers and multi-parameter MRI that resemble those observed in Alzheimer's disease, offering a theoretical foundation for early clinical intervention in SCD.

Ginsenoside Rg1 promotes β‑amyloid peptide degradation through inhibition of the ERK/PPARγ phosphorylation pathway in an Alzheimer's disease neuronal model.

β-Amyloid peptide (Aβ) deposition in the brain is an important pathological change in Alzheimer's disease (AD). Insulin-degrading enzyme (IDE), which is regulated transcriptionally by peroxisome proliferator-activated receptor γ (PPARγ), is able to proteolyze Aβ. One of the members of the MAPK family, ERK, is able to mediate the phosphorylation of PPARγ at Ser112, thereby inhibiting its transcriptional activity. Ginsenoside Rg1 is one of the active ingredients in the natural medicine ginseng and has inhibitory effects on Aβ production. The present study was designed to investigate whether ginsenoside Rg1 is able to affect the regulation of PPARγ based on the expression of its target gene, IDE, and whether it is able to promote Aβ degradation via inhibition of the ERK/PPARγ phosphorylation pathway. In the present study, primary cultured rat hippocampal neurons were treated with Aβ1-42, ginsenoside Rg1 and the ERK inhibitor PD98059, and subsequently TUNEL staining was used to detect the level of neuronal apoptosis. ELISA was subsequently employed to detect the intra- and extracellular Aβ1-42 levels, immunofluorescence staining and western blotting were used to detect the translocation of ERK from the cytoplasm to the nucleus, immunofluorescence double staining was used to detect the co-expression of ERK and PPARγ, and finally, western blotting was used to detect the phosphorylation of PPARγ at Ser112 and IDE expression. The results demonstrated that ginsenoside Rg1 or PD98059 were able to inhibit primary cultured hippocampal neuron apoptosis induced by Aβ1-42 treatment, reduce the levels of intra- and extraneuronal Aβ1-42 and inhibit the translocation of ERK from the cytoplasm to the nucleus. Furthermore, administration of ginsenoside Rg1 or PD98059 resulted in attenuated co-expression of ERK and PPARγ, inhibition of phosphorylation of PPARγ at Ser112 mediated by ERK and an increase in IDE expression. In addition, the effects when PD98059 to inhibit ERK followed by treatment with ginsenoside Rg1 were found to be more pronounced than those when using PD98059 alone. In conclusion, ginsenoside Rg1 was demonstrated to exert neuroprotective effects on AD via inhibition of the ERK/PPARγ phosphorylation pathway, which led to an increase in IDE expression, the promotion of Aβ degradation and the decrease of neuronal apoptosis. These results could provide a theoretical basis for the clinical application of ginsenoside Rg1 in AD.

Physical Performance and Amyloid-β in Humans: A Systematic Review and Meta-Analysis of Observational Studies.

Accumulation of amyloid-β (Aβ) plaques is one of the main features of Alzheimer's disease (AD). Physical performance has been related to dementia risk and Aβ, and it has been hypothesized as one of the mechanisms leading to greater accumulation of Aβ. Yet, no evidence synthesis has been performed in humans. To investigate the association of physical performance with Aβ in humans, including Aβ accumulation on brain, and Aβ abnormalities measured in cerebrospinal fluid (CSF) and blood. A systematic review with multilevel meta-analysis was performed from inception to June 16th, 2022. Studies were eligible if they examined the association of physical performance with Aβ levels, including the measure of physical performance as a predictor and the measure of Aβ as an outcome in humans. 7 articles including 2,619 participants were included in the meta-analysis. The results showed that physical performance was not associated with accumulation of Aβ in the brain (ES = 0.01; 95% CI -0.21 to 0.24; I2 = 69.9%), in the CSF (ES = -0.28; 95% CI -0.98 to 0.41; I2 = 91.0%) or in the blood (ES = -0.19; 95% CI -0.61 to 0.24; I2 = 99.75%). Significant heterogeneity was found across the results , which posed challenges in arriving at consistent conclusions; and the limited number of studies hindered the opportunity to conduct a moderation analysis. The association between physical performance and Aβ is inconclusive. This uncertainly arises from the limited number of studies, study design limitations, and heterogeneity of measurement approaches. More studies are needed to determine whether physical performance is related to Aβ levels in humans.

Physical activity and brain amyloid beta: A longitudinal analysis of cognitively unimpaired older adults.

The current study evaluated the relationship between habitual physical activity (PA) levels and brain amyloid beta (Aβ) over 15 years in a cohort of cognitively unimpaired older adults. PA and Aβ measures were collected over multiple timepoints from 731 cognitively unimpaired older adults participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Aging. Regression modeling examined cross-sectional and longitudinal relationships between PA and brain Aβ. Moderation analyses examined apolipoprotein E (APOE) ε4 carriage impact on the PA-Aβ relationship. PA was not associated with brain Aβ at baseline (β=-0.001, p=0.72) or over time (β=-0.26, p=0.24). APOE ε4 status did not moderate the PA-Aβ relationship over time (β=0.12, p=0.73). Brain Aβ levels did not predict PA trajectory (β=-54.26, p=0.59). Our study did not identify a relationship between habitual PA and brain Aβ levels. Physical activity levels did not predict brain amyloid beta (Aβ) levels over time in cognitively unimpaired older adults (≥60 years of age). Apolipoprotein E (APOE) ε4 carrier status did not moderate the physical activity-brain Aβ relationship over time. Physical activity trajectories were not impacted by brain Aβ levels.

Curcumin alleviates Alzheimer’s disease by inhibiting inflammatory response, oxidative stress and activating the AMPK pathway

BackgroundAlzheimer’s disease (AD) is a common degenerative brain disorder with limited therapeutic options. Curcumin (Cur) exhibits neuroprotective function in many diseases. We aimed to explore the role and mechanism of Cur in AD. Materials and MethodsFirstly, we established AD mice by injecting amyloid-β1–42 (Aβ1–42) solution into the hippocampus. Then, the AD mice received 150 mg/kg/d Cur for 10 consecutive days. The Morris water maze test was conducted to evaluate the cognitive function of the mice by hidden platform training and probe trials. To assess the spatial memory of the mice, spontaneous alternation behavior, the number of crossing the novel arm and the time spent in the novel arm during the Y-maze test was recorded. Hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNAL) assay were performed to assess the pathological damage and apoptosis of brain tissues. The number of damaged neurons was inspected by Nissl staining. Immunohistochemical staining was then performed to detect Aβ1–42 deposition. The levels of tumor necrosis factor-α (TNF-a), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in serum and hippocampus, the contents of super oxide dismutase (SOD) and malondialdehyde (MDA) in brain tissues were assessed by enzyme-linked immunosorbent assay (ELISA). Additionally, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), RelA (p65) protein expressions and Adenosine 5′-monophosphate-activated protein kinase (AMPK) phosphorylation were tested using Western blot. ResultsCur not only improved cognitive function and spatial memory, but also alleviated the pathological damage and apoptosis of brain tissues for AD mice. Meanwhile, upon Cur treatment, the number of damaged neurons in AD mice was decreased, the level of Aβ1–42 in AD mice was significantly decreased. Furthermore, the AD mice treated with Cur exhibited lower TNF-a, IL-6, IL-1β and MDA levels and a higher SOD content. Besides, Cur also downregulated p65 expression and upregulated AMPK phosphorylation. ConclusionCur may improve AD via suppressing the inflammatory response, oxidative stress and activating the AMPK pathway, suggesting that Cur may be a potential drug for AD.

Cyanidin-3-O-glucoside protects the brain and improves cognitive function in APPswe/PS1ΔE9 transgenic mice model

Cyanidin-3-O-glucoside (C3G) is a natural anthocyanin with antioxidant, anti-inflammatory, and antitumor properties. However, as the effects of C3G on the amyloidogenic pathway, autophagy, tau phosphorylation, neuronal cell death, and synaptic plasticity in Alzheimer’s disease models have not been reported, we attempted to investigate the same in the brains of APPswe/PS1ΔE9 mice were analyzed. After oral administration of C3G (30 mg/kg/day) for 16 weeks, the cortical and hippocampal regions in the brains of APPswe/PS1ΔE9 mice were analyzed. C3G treatment reduced the levels of soluble and insoluble Aβ (Aβ40 and Aβ42) peptides and reduced the protein expression of the amyloid precursor protein, presenilin-1, and β-secretase in the cortical and hippocampal regions. And C3G treatment upregulated the expression of autophagy-related markers, LC3B-II, LAMP-1, TFEB, and PPAR-α and downregulated that of SQSTM1/p62, improving the autophagy of Aβ plaques and neurofibrillary tangles. In addition, C3G increased the protein expression of phosphorylated-AMPK/AMPK and Sirtuin 1 and decreased that of mitogen-activated protein kinases, such as phosphorylated-Akt/Akt and phosphorylated-ERK/ERK, thus demonstrating its neuroprotective effects. Furthermore, C3G regulated the PI3K/Akt/GSK3β signaling by upregulating phosphorylated-Akt/Akt and phosphorylated-GSK3β/GSK3β expression. C3G administration mitigated tau phosphorylation and improved synaptic function and plasticity by upregulating the expression of synapse-associated proteins synaptophysin and postsynaptic density protein-95. Although the potential of C3G in the APPswe/PS1ΔE9 mouse models has not yet been reported, oral administration of the C3G is shown to protect the brain and improve cognitive behavior.Graphical

Self-calibrating surface-enhanced Raman scattering-lateral flow immunoassay for determination of amyloid-β biomarker of Alzheimer's disease

Rapid early diagnosis of Alzheimer's disease (AD) is critical for its effective and prompt treatment since the clinically available treatments can only relieve the symptoms or slow the disease progression. However, it is still a grand challenge to accurately diagnose AD at its early stage because of the indiscernible early symptoms and the lack of sensitive detection tools. Here, we develop a self-calibrating surface-enhanced Raman scattering (SERS)-lateral flow immunoassay (LFIA) biosensor for quantitative analysis of amyloid-β1-42 (Aβ1-42) biomarker in biofluids, enabling accurate AD diagnosis. The designed SERS-LFIA biosensor makes full use of the unique aspects of the LFIA format and the SERS technique to quantify the Aβ1-42 level in complex biofluids with high sensitivity, excellent anti-interference capability, low-cost, and operation simplicity. The key aspect of the design of this biosensor is that internal standard (IS)-SERS nanoparticles are embedded in the test line of the test strip as a self-calibration unit for correction of fluctuations of SERS signals caused by various external factors such as test parameters and sample heterogeneity. We demonstrate significant improvement of the detection performance of the SERS-LFIA biosensor for ratiometric quantification of Aβ1-42 owing to the built-in IS in the test line. We expect that the present IS-based biosensing strategy provides a promising tool for accurate AD diagnosis and longitudinal monitoring of therapeutic response with great promises for clinical translation.

Two Phase 3 Trials of Gantenerumab in Early Alzheimer’s Disease

BackgroundMonoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer’s disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer’s disease.MethodsWe conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer’s disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116.ResultsA total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, –0.31; 95% confidence interval [CI], –0.66 to 0.05; P=0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, –0.19; 95% CI, –0.55 to 0.17; P=0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was –66.44 and –56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%.ConclusionsAmong persons with early Alzheimer’s disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann–La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.)

Neuronal transcriptome, tau and synapse loss in Alzheimer’s knock-in mice require prion protein

BackgroundProgression of Alzheimer’s disease leads to synapse loss, neural network dysfunction and cognitive failure. Accumulation of protein aggregates and brain immune activation have triggering roles in synaptic failure but the neuronal mechanisms underlying synapse loss are unclear. On the neuronal surface, cellular prion protein (PrPC) is known to be a high-affinity binding site for Amyloid-β oligomers (Aβo). However, PrPC’s dependence in knock-in AD models for tau accumulation, transcriptomic alterations and imaging biomarkers is unknown.MethodsThe necessity of PrPC was examined as a function of age in homozygous AppNL−G−F/hMapt double knock-in mice (DKI). Phenotypes of AppNL−G−F/hMapt mice with a deletion of Prnp expression (DKI; Prnp−/−) were compared with DKI mice with intact Prnp, mice with a targeted deletion of Prnp (Prnp−/−), and mice with intact Prnp (WT). Phenotypes examined included behavioral deficits, synapse loss by PET imaging, synapse loss by immunohistology, tau pathology, gliosis, inflammatory markers, and snRNA-seq transcriptomic profiling.ResultsBy 9 months age, DKI mice showed learning and memory impairment, but DKI; Prnp−/− and Prnp−/− groups were indistinguishable from WT. Synapse loss in DKI brain, measured by [18F]SynVesT-1 SV2A PET or anti-SV2A immunohistology, was prevented by Prnp deletion. Accumulation of Tau phosphorylated at aa 217 and 202/205, C1q tagging of synapses, and dystrophic neurites were all increased in DKI mice but each decreased to WT levels with Prnp deletion. In contrast, astrogliosis, microgliosis and Aβ levels were unchanged between DKI and DKI; Prnp−/− groups. Single-nuclei transcriptomics revealed differential expression in neurons and glia of DKI mice relative to WT. For DKI; Prnp−/− mice, the majority of neuronal genes differentially expressed in DKI mice were no longer significantly altered relative to WT, but most glial DKI-dependent gene expression changes persisted. The DKI-dependent neuronal genes corrected by Prnp deletion associated bioinformatically with synaptic function. Additional genes were uniquely altered only in the Prnp−/− or the DKI; Prnp−/− groups.ConclusionsThus, PrPC-dependent synapse loss, phospho-tau accumulation and neuronal gene expression in AD mice can be reversed without clearing Aβ plaque or preventing gliotic reaction. This supports targeting the Aβo-PrPC interaction to prevent Aβo-neurotoxicity and pathologic tau accumulation in AD.

Circulating amyloid-beta 1-40 levels associate with cardiac remodelling and myocardial recovery in advanced heart failure

Abstract Background A subgroup of left ventricular assist device (LVAD) patients may present reverse remodeling and myocardial recovery, but prognostic and therapeutic biomarkers are lacking. Amyloid-β 1-40 (Aβ1-40), a 40 amino-acid long peptide, has been associated with myocardial ageing, cardiac remodeling, increased risk for HF and worse outcomes in HF patients. Purpose To evaluate the associations between circulating Aβ1-40 and: a) markers of myocardial remodeling and hemodynamic status in advanced HF and b) post-LVAD myocardial unloading and recovery. Methods Plasma Αβ1-40, by ELISA was measured in 98 consecutive patients with advanced HF prior LVAD implantation and in 20 of them at 3-12 months after LVAD implantation. Response to LVAD was defined as LVEF &amp;gt;40% and LV end-diastolic diameter≤ 59 mm at 3 to 1 months after. Results Most of the patients were male (N = 84, 85.7%), relatively young (mean age = 57.16 years, SD = 16.30), with median duration of HF symptoms of 72 months [interquartile range = 13.49-120). After multivariable adjustment for biologically plausible confounders, Aβ1-40 was independently associated with RAP (18.7% increase per 1-SD increase of Αβ1-40), PCWP (12.6% increase per 1-SD increase of Αβ1-40), LVEF (8.5% decrease per 1-SD increase of Αβ1-40) and estimated arterial stiffness as calculated by estimated pulse wave velocity (ePWV, 2.9% increase per 1-SD increase of Αβ1-40) (log-level regression model). Aβ1-40 was independently associated with hemodynamic parameters, LVEF and ePWV (generalized linear model). Responders significantly decreased circulating levels of Aβ1-40 compared to non-responders (p for interaction = 0.013). By linear mixed model analysis, changes in Αβ1-40 were independently associated with changes in RAP (mean change = 1.35 mmHg per 1-SD change in Aβ1-40, (0.211-2.48), p = 0.02) and PCWP (mean change = 1.61mmHg per 1-SD change in Aβ1-40, (0.191-3.02), p = 0.026), while a marginal association was observed with ePWV (p = 0.063). Discussion Circulating Αβ1-40 is associated with myocardial recovery after LVAD support, while changes in Aβ1-40 were independently associated with changes in right and left ventricular pre-load. From a mechanistic point of view, our findings are supported by current literature and warrant further research to clarify the role of this peptide as a biomarker of hemodynamic deterioration and myocardial recovery after LVAD implantation. Figure. A) Associations of Aβ1-40 with hemodynamic parameters in advanced heart failure patients prior to LVAD implantation. Standardized coefficient represents the number of standard deviations the dependent variable will change per one standard deviation increase in Aβ1-40. Generalized linear model adjusted for age, gender, eGFR, duration of heart failure symptoms cardiac index and Aβ1-40. B) Prospective changes of Aβ1-40 in responders vs non-responders. Mean difference= -55pg/mL, (-98.3, -11.8), p for interaction = 0.013.

Serum immunoglobulins and biomarkers of dementia: a population-based study

BackgroundInflammation plays a key role in the development of dementia, but its link to early biomarkers, particularly those in plasma or neuroimaging, remains elusive. This study aimed to investigate the association between serum immunoglobulins and biomarkers of dementia.MethodsBetween 1997 and 2009, serum immunoglobulins (IgA, IgG and IgM) were measured in dementia-free participants of the population-based Rotterdam Study. A random subset of participants had assessment of biomarkers in plasma (total tau (t-tau), neurofilament light chain (NfL), amyloid-β40 (Aβ-40), amyloid-β42 (Aβ-42), while another subset of participants underwent neuroimaging to quantify brain volume, white matter structural integrity and markers of cerebral small vessel disease. Linear regression models were constructed to determine cross-sectional associations between IgA, IgG, IgM and biomarkers of dementia, with adjustment for potential confounders. Multiple testing correction was applied using the false discovery rate. As a sensitivity analysis, we re-ran the models for participants within the reference range of immunoglobulins, excluding those using immunomodulating drugs, and conducted a stratified analysis by APOE-ε4 carriership and sex.ResultsOf 8,768 participants with serum immunoglobulins, 3,455 participants (65.8 years [interquartile range (IQR): 61.5–72.0], 57.2% female) had plasma biomarkers available and 3,139 participants (57.4 years [IQR: 52.7–60.7], 54.4% female) had neuroimaging data. Overall, no associations between serum immunoglobulins and biomarkers of dementia remained significant after correction for multiple testing. However, several suggestive associations were noted: higher serum IgA levels concurred with lower plasma levels of Aβ-42 (standardized adjusted mean difference: -0.015 [95% confidence interval (CI): -0.029−-0.002], p = 2.8 × 10–2), and a lower total brain volume, mainly driven by less gray matter (-0.027 [-0.046−-0.008], p = 6.0 × 10–3) and more white matter hyperintensities (0.047 [0.016 – 0.077], p = 3.0 × 10–3). In sensitivity analyses, higher IgM was linked to lower t-tau, Aβ-40, and Aβ-42, but also a loss of white matter microstructural integrity. Stratified analyses indicate that these associations potentially differ between carriers and non-carriers of the APOE-ε4 allele and men and women.ConclusionsWhile associations between serum immunoglobulins and early markers of dementia could not be established in this population-based sample, it may be valuable to consider factors such as APOE-ε4 allele carriership and sex in future investigations.

Tanshinone IIA, the key compound in Salvia miltiorrhiza, improves cognitive impairment by upregulating Aβ-degrading enzymes in APP/PS1 mice

In Alzheimer's disease (AD), amyloid-beta (Aβ) plays a crucial role in pathogenesis. Clearing Aβ from the brain is considered as a key therapeutic strategy. Previous studies indicated that Salvia miltiorrhiza (Danshen) could protect against AD. However, the main anti-AD components in Danshen and their specific mechanisms are not clear. In this study, pharmacological network analysis indicated that Tanshinone IIA (Tan IIA) was identified as the key active compound in Danshen contributing to protect against AD. Then, APP/PS1 double transgenic mice were employed to examine the neuroprotective effect of Tan IIA. APP/PS1 mice (age, 6 months) were administered (10 and 20 mg/kg) for 8 weeks. Tan IIA improved learning and anxiety behaviors in APP/PS1 mice. Furthermore, Tan IIA reduced oxidative stress, inhibited neuronal apoptosis, improved cholinergic nervous system and decreased endoplasmic reticulum stress in the brain of APP/PS1 mice. Moreover, Tan IIA treatment reduced the level of Aβ. Molecular docking result showed that Tan IIA might block AD by upregulating Aβ-degrading enzymes. Western blot results confirmed that the expressions of insulin degrading enzymes (IDE) and neprilysin (NEP) were significantly increased after Tan IIA treatment, which demonstrated that Tan IIA improved AD by increasing Aβ-degrading enzymes.

A rat model established by simulating genetic–environmental interactions recapitulates human Alzheimer's disease pathology

BackgroundIn humans, Alzheimer’s disease (AD) is typically sporadic in nature, and its pathology is usually influenced by extensive factors. The study established a rat model based on the genetic–environmental interaction. MethodsA rat model was established by transduction of an adeno-associated virus combined with acrolein treatment. Rats were assigned to the normal control (NC), acrolein group, AAV (-) group, AAV-APP group, and AAV-APP/acrolein group. The success of model construction was verified in multiple ways, including by assessing cognitive function, examining microstructural changes in the brain in vivo, and performing immunohistochemistry. The contribution of genetic (APP mutation) and environmental (acrolein) factors to AD-like phenotypes in the model was explored by factorial analysis. Results1) The AAV-APP/acrolein group showed a decline in cognitive function, as indicated by a reduced gray matter volume in key cognition-related brain areas, lower FA values in the hippocampus and internal olfactory cortex, and Aβ deposition in the cortex and hippocampus. 2) The AAV-APP group also showed a decline in cognitive function, although the group exhibited atypical brain atrophy in the gray matter and insignificant Aβ deposition. 3) The acrolein group did not show any significant changes in Aβ levels, gray matter volume, or cognitive function. 4) The genetic factor (APP mutation) explained 39.74% of the AD-like phenotypes in the model factors, and the environmental factor (acrolein exposure) explained 33.3%. ConclusionsThe genetic–environmental interaction rat model exhibited a phenotype that resembled the features of human AD and will be useful for research on AD.

Linking Cognitive Impairment with Amyloid-β Accumulation in Alzheimer's Disease: Insights from Behavioral Tests and FTIR Spectroscopy.

Alzheimer's disease (AD) is a neurodegenerative disorder that progresses over time. Fourier Transform Infrared Spectroscopy (FTIR) analysis gives identification of the main metabolic changes that happen during neurodegeneration, by monitoring biochemical and molecular structure alterations that can help in AD diagnosis or treatment approach. The aim of the present work is to assess AD hallmarks in molecular structure of retina and monitor accumulation of amyloid beta42(Aβ42) in brain and retina during disease progression. AD induced in rats by Aluminum Chloride (AlCl3). Retinal molecular structure during disease progression for 2,4,6 and 8 weeks was assessed by Fourier-transform infrared spectroscopy (FTIR) and the incidence of the disease was confirmed by a behavioural assessment; the Morris Water Maze test. Aβ42 levels in the brain and retina were also measured. The results indicated that cognitive impairment starting from 6 weeks of AlCl3 administration. Retinal concentration of Aβ42 was significant increase (p < 0.05) from 2 weeks that precedes the observed increase of Aβ42 in the brain which appeared after 4 weeks of AlCl3 administration. Multivariate principal component analysis discovers that the variance noticed in the infrared spectra due to AD condition and it is time dependent for progression of the disease. The accumulation of Aβ42 is a sensitive early biomarker in retina for AD. FTIR analysis of the retina revealed changes in hydrogen bond formation or destruction, alterations in lipid chain length and branching accompanied by depleted lipid content and carbonization, as well as degeneration of the retinal tissue due to AD.

96 The Proportion of Patients with Cerebrospinal Fluid Biomarkers Consistent with Alzheimer’s Disease in a Cohort with Suspected Normal Pressure Hydrocephalus

Objective:Normal pressure hydrocephalus (NPH) is characterized by pathologically enlarged ventricles without elevated cerebrospinal fluid (CSF) pressure along with a triad of clinical symptoms including gait disturbances, urinary incontinence, and cognitive impairment. NPH is evaluated with lumbar drain trials (LDTs) where CSF is removed over several days to determine if patients would benefit from ventricular shunting. Candidate selection and success for these surgeries remains challenging because other diseases such as Alzheimer’s disease (AD) share common features with NPH in cognitive impairment and enlarged ventricles. Prior research has found that 20%-40% of presumed NPH cases have AD pathology as determined by brain biopsy or autopsy. CSF biomarkers of AD can be altered in NPH and are not always conclusive, complicating the interpretation of results when formulating diagnoses and prognoses. Studies to refine the analyses of AD CSF biomarkers in NPH are needed. We aimed to examine the frequency of CSF biomarker results among patients presenting for NPH evaluations with LDTs.Participants and Methods:62 patients presented for LDTs upon physician recommendations. CSF specimens were sent to Mayo Clinic Laboratories for Alzheimer Disease Evaluation (ADEVL) that utilizes Elecsys (Lenexa, KS) CSF electrochemiluminescence immunoassays (Roche Diagnostics, Basel, Switzerland) to measure levels of amyloid-beta 42 (Aβ42), total tau (t-tau), and phosphorylatedtau (p-tau), and p-tau:Aβ42 ratio. Results were classified based on interpretation through the Amyloid/Tau/Neurodegeneration (ATN) framework1: 1) AD - biomarker profile consistent with AD pathologic change, 2) non-AD profile - biomarker levels normal or inconsistent with AD pathologic change, or 3) indeterminate - biomarkers were incongruous with only one or two abnormal levels of Aβ42, t-tau, p-tau, or ptau: Aβ42. Indeterminate cases may represent altered protein levels due to CSF dynamics or AD-related pathologic change. In reviewing recent research on CSF dynamics and AD biomarkers in NPH2 a p-tau threshold of 15 pg/mL was derived and implemented such that cases with Aß42 &lt;=1026 pg/mL and p-tau &lt;15 pg/mL were designated as suspected non-AD, and those with Aß42 &lt;=1026 pg/mL and p-tau &gt;15 pg/mL were designated suspected AD.Results:Of the 62 LDT cases, 12 (19.35%) were classified as AD, 31 (50%) were indeterminate and 22 (35.48%) were non-AD. Of the 31 indeterminate cases, 21 (33.87% of the overall sample) were suspected non-AD and 7 (11.29% of the full sample) were categorized as suspected AD.Conclusions:Our findings show that 20%-30% of patients presenting for LDT showed evidence for AD-type pathologic change, consistent with prior reports of AD pathology in cases of possible NPH. Half of all LDT cases had indeterminate AD CSF biomarker results, the interpretations of which were confounded by the potential alterations of CSF biomarkers levels due to NPH independent of AD. Our findings emphasize the need to establish better approaches to interpreting CSF AD biomarkers in evaluating NPH. Future research should examine the discriminative utility of CSF AD biomarkers and the selected p-tau threshold in indeterminate cases for predicting response to LDT and shunting.

Synergetic effect of matrine on the catalytic scFv antibody HS72 in vitro and in mice with Alzheimer disease pathology

Single-chain variable fragment (scFv) HS72 is a catalytic antibody that specifically degrades amyloid β-protein 1–42 (Aβ42) aggregates in vitro or reduces the level or burden of Aβ42 deposits/plaques in the brains of mice with Alzheimer disease pathology. Its efficacy has been shown in protecting neural cells in vitro and improving the morphology of the cell population in the brain of mice with AD pathology (AD mice). Matrine (Mat) is a natural product capable of binding to Aβ42 or its aggregates and blocking their neurotoxicity at concentrations of at least 10 μM or greater. However, this study revealed a synergistic effect of Mat on the catalytic effect of HS72 at low concentrations (0.01−2.5 μM). This is evidenced by the fact that Mat synergistically enhances HS72's ability to degrade Aβ42 aggregates and protect neural cells (SH-SY5Y and HT22 cells, and brain cells of AD mice). The molecular docking models and characterization of Mat's action both indicated that the mechanism of Mat's synergistic impact on HS72 catalysis is to increase the turnover number (or molecular activity) of HS72 by enhancing the catalytic power of the HS72's catalytic groups and encouraging the release of the degradation products (Aβ fragments). The study's results suggest a natural synergy between Mat-like small molecules and the catalytic anti-oligomeric Aβ42 antibody HS72, enabling more effective reduction or removal of Aβ42 aggregates or plaques than the antibody alone. These findings provide novel insights into the effectiveness of anti-oligomeric Aβ42 antibodies in AD immunotherapy.

APOE genotype and sex modulate Alzheimer's disease pathology in aged EFAD transgenic mice.

Increasing evidence supports that age, APOE and sex interact to modulate Alzheimer's disease (AD) risk, however the underlying pathways are unclear. One way that AD risk factors may modulate cognition is by impacting amyloid beta (Aβ) accumulation as plaques, and/or neuroinflammation Therefore, the goal of the present study was to evaluate the extent to which age, APOE and sex modulate Aβ pathology, neuroinflammation and behavior in vivo. To achieve this goal, we utilized the EFAD mice, which express human APOE3 or APOE4 and have five familial AD mutations (FAD) that result in Aβ42 overproduction. We assessed Aβ levels, reactive glia and Morris water maze performance in 6-, 10-, 14-, and 18-month-old EFAD mice. Female APOE4 mice had the highest Aβ deposition, fibrillar amyloid deposits and neuroinflammation as well as earlier behavior deficits. Interestingly, we found that female APOE3 mice and male APOE4 mice had similar levels of pathology. Collectively our data support that the combination of APOE4 and female sex is the most detrimental combination for AD, and that at older ages, female sex may be equivalent to APOE4 genotype.

Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis and has been implicated in several neuronal disorders or neuronal injuries. Ligands targeting the mitochondrial translocator protein (18 kDa), promote neurosteroidogenesis and may be neuroprotective. To study whether the TSPO ligand XBD173 may exert early neuroprotective effects in AD pathology we investigated the impact of XBD173 on amyloid toxicity and neuroplasticity in mouse models of AD. We show that XBD173 (emapunil), via neurosteroid-mediated signaling and delta subunit-containing GABAA receptors, prevents the neurotoxic effect of Aβ on long-term potentiation (CA1-LTP) in the hippocampus and prevents the loss of spines. Chronic but not acute administration of XBD173 ameliorates spatial learning deficits in transgenic AD mice with arctic mutation (ArcAβ). The heterozygous TSPO-knockout crossed with the transgenic arctic mutation model of AD mice (het TSPOKO X ArcAβ) treated with XBD173 does not show this improvement in spatial learning suggesting TSPO is needed for procognitive effects of XBD173. The neuroprotective profile of XBD173 in AD pathology is further supported by a reduction in plaques and soluble Aβ levels in the cortex, increased synthesis of neurosteroids, rescued spine density, reduction of complement protein C1q deposits, and reduced astrocytic phagocytosis of functional synapses both in the hippocampus and cortex. Our findings suggest that XBD173 may exert therapeutic effects via TSPO in a mouse model of AD.

Cognitive Profile in Parkinson’s Disease Dementia Patients with Low versus Normal Cerebrospinal Fluid Amyloid Beta

Introduction: In patients with Parkinson’s disease (PD), low cerebrospinal fluid (CSF) amyloid beta 1-42 (Ab42) at baseline is the most consistent CSF biomarker as a risk factor for developing dementia. Low CSF Ab42 is, however, a typical hallmark of Alzheimer’s disease (AD). Hence, low CSF Ab42 in patients with PD may indicate presence of comorbid AD pathology and may predict a more AD-like cognitive profile when they develop dementia. Our study aimed to investigate if low CSF Ab42 at baseline is associated with a more AD-like cognitive profile in PD patients with dementia. Methods: In a prospectively followed-up, population-based cohort of newly diagnosed PD patients, we compared the cognitive profile of dementia in those with a low CSF Ab42 level at baseline with that of patients who had normal levels at the time when they developed dementia. Four different cognitive domain z-scores (memory, attention, executive, visuospatial) were calculated. Patients were subdivided into three tertiles or categorized dichotomously based on the baseline CSF Ab42 levels as measured by electrochemiluminescence and ELISA. Results: During 10-year follow-up, 37 patients met the inclusion criteria. Memory domain composite z-scores, memory subtest z-scores, and the difference between long-delay free recall versus recognition scores were not significantly different between the groups. Composite z-scores of visuospatial functions significantly differed between the tertiles, which was not significant after Bonferroni correction. In the dichotomous group analysis, z-scores of visuospatial functions significantly differed between the two groups. The other cognitive domain z-scores were not significantly different. Conclusions: In patients with PD dementia, low CSF Ab42 level at baseline is not associated with a specific cognitive profile.