Aβ Deposition In Brain Research Articles

Misfolded amyloid-β strains and their potential roles in the clinical and pathological variability of Alzheimer's disease.

Misfolded amyloid-β strains and their potential roles in the clinical and pathological variability of Alzheimer's disease.

APOE Antibody Inhibits Aβ-Associated Tau Seeding and Spreading in a Mouse Model.

APOE is the strongest genetic factor for late-onset Alzheimer's disease (AD). A specific conformation of the ApoE protein is present in amyloid-β (Aβ) containing plaques. Immunotherapy targeting ApoE in plaques reduces brain Aβ deposits in mice. Here, we evaluated the effects of the anti-human APOE antibody HAE-4 on amyloid plaques, Aβ-mediated tau seeding and spreading, and neuritic dystrophy in the 5XFAD amyloid mice expressing human ApoE4. HAE-4 reduced Aβ plaques as well as Aβ-driven tau seeding/spreading and neuritic dystrophy. These results demonstrate that HAE-4 may provide therapeutic effects on amyloid removal and Aβ driven downstream consequences such as tauopathy. ANN NEUROL 2022;91:847-852.

Non-linear Character of Plasma Amyloid Beta Over the Course of Cognitive Decline in Alzheimer’s Continuum

Plasma amyloid-β (Aβ) was associated with brain Aβ deposition and Alzheimer’s disease (AD) development. However, changes of plasma Aβ over the course of cognitive decline in the Alzheimer’s continuum remained uncertain. We recruited 449 participants to this study, including normal controls (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD, and non-AD dementia. All the participants underwent plasma Aβ42, Aβ40, and t-tau measurements with single-molecule array (Simoa) immunoassay and PET scan with 18F-florbetapir amyloid tracer. In the subgroup of Aβ-PET positive, plasma Aβ42 and Aβ42/Aβ40 ratio was significantly lower in AD than NC, SCD and MCI, yet SCD had significantly higher levels of plasma Aβ42 than both NC and MCI. In the diagnostic groups of MCI and dementia, participants with Aβ-PET positive had lower plasma Aβ42 and Aβ42/40 ratio than participants with Aβ-PET negative, and the increasing levels of plasma Aβ42 and Aβ42/40 ratio indicated lower risks of Aβ-PET positive. However, in the participants with SCD, plasma Aβ42 and Aβ40 were higher in the subgroup of Aβ-PET positive than Aβ-PET negative, and the increasing levels of plasma Aβ42 and Aβ40 indicated higher risks of Aβ-PET positive. No significant association was observed between plasma Aβ and Aβ-PET status in normal controls. These findings showed that, in the continuum of AD, plasma Aβ42 had a significantly increasing trend from NC to SCD before decreasing in MCI and AD. Furthermore, the predictive values of plasma Aβ for brain amyloid deposition were inconsistent over the course of cognitive decline.

Biochanin A alleviates cognitive impairment and hippocampal mitochondrial damage in ovariectomized APP/PS1 mice

BackgroundEstrogen deficiency leads to mitochondrial defects that precede Alzheimer's disease (AD)-associated pathological changes in a postmenopausal mouse model. Biochanin A (BCA) is a phytoestrogen isolated from Trifolium pratense L. used to relieve postmenopausal problems in women. In previous work, we observed that oral BCA treatment led to neuroprotection in an ovariectomized rat model. The objective of this study was to investigate whether and how BCA protects against hippocampal mitochondrial damage in a postmenopausal model of AD. MethodAPP/PS1 mice underwent bilateral ovariectomy and then, seven days later, received oral BCA at 20 or 40 mg/kg, or oral estradiol at 0.5 mg/kg, daily for 90 days. Sham animals were not ovariectomized and received no additional treatments. Cognitive function was examined using the passive avoidance task, novel object recognition test, and Morris water maze test. The level of circulating estrogen in vivo was assessed indirectly by measuring the wet weight of the uterus. We detected Aβ deposition and PGC-1α in brain by immunohistochemistry; p62, by immunofluorescence; and ERα, ERβ, PGC-1α, NRF1, mtTFA, Drp1, OPA1, Mfn2, Beclin1, LC3B, Pink1, and Parkin by immunoblotting. ResultsBCA treatment rescued cognitive decline and reduced Aβ deposition and BACE1 expression in the hippocampus of ovariectomized APP/PS1 mice. BCA reversed the imbalance of mitochondrial dynamics caused by ovariectomy by increasing the expression of phospho-Drp1 (ser637), OPA1, and Mfn2. BCA reversed abnormal mitophagy induced by ovariectomy by increasing the expression of Beclin1, LC3B, Pink1, and Parkin, as well as by reducing the expression of p62. ConclusionsBCA treatment enhances learning and memory abilities and alleviates AD symptoms in a postmenopausal model of AD. A possible mechanism is that BCA rescues the reduction of mitochondrial biogenesis, imbalance of mitochondrial dynamics, and abnormal mitophagy caused by ovariectomy. This study supports further research on BCA to develop treatments for postmenopausal women with AD.

Insights on amyloid-related imaging abnormalities from the “Pre-Alzheimer’s disease Alliance of China”

Alzheimer’s disease (AD) is the most common cause of dementia and accounts for 60 – 80% of all such cases. For approximately 20 years, the research and development of new drugs for AD all ended in failure; however, aducanumab was recently granted accelerated approval by the US Food and Drug Administration. Aducanumab is a representative passive anti-β-amyloid (Aβ) immunotherapy and is the only approved drug that directly targets the pathological changes of AD; it can significantly reduce brain Aβ deposition, which is a hallmark of AD. During the clinical trials of amyloid-targeting monoclonal antibodies, represented by aducanumab, amyloid-related imaging abnormalities (ARIA) were the most common and important adverse reactions. Therefore, before the large-scale clinical application of amyloid-targeting monoclonal antibodies, clinicians and radiologists need to fully understand ARIA so that they can make more informed decisions. Considering the very uneven distribution of medical resources in China, we — on behalf of the “Pre-AD Alliance of China” — believe that it is necessary to write a consensus to elaborate on the mechanisms, risk factors, identification methods, and administration processes of ARIA.

TAPPing into the potential of inducible tau/APP transgenic mice.

Our understanding of the pathological interactions between amyloidosis and tauopathy in Alzheimer's disease is incomplete. We sought to determine if the relative timing of the amyloidosis and tauopathy is critical for amyloid-enhanced tauopathy. We crossed an inducible tauopathy model with two β-amyloid models utilising the doxycycline-repressible transgenic system to modulate timing and duration of human tau expression in the context of amyloidosis and then assessed tauopathy, amyloidosis and gliosis. We combined inducible rTg4510 tau with APPswe/PS1dE9 [Line 85 (L85)] mice to examine the interactions between Aβ and tauopathy at different stages of amyloidosis. When we initially suppressed mutant human tau expression for 14-15 months and subsequently induced tau expression for 6months, severe amyloidosis with robust tauopathy resulted in rTg4510/L85 but not rTg4510 mice. When we suppressed mutant tau for 7months before inducing expression for a subsequent 6months in another cohort of rTg4510/L85 and rTg4510 mice, only rTg4510/L85 mice displayed robust tauopathy. Lastly, we crossed rTg4510 mice to tet-regulated APPswe/ind [Line 107 (L107)] mice, using doxycycline to initially suppress both transgenes for 1month before inducing expression for 5months to model early amyloidosis. In contrast to rTg4510, rTg4510/L107 mice rapidly developed amyloidosis, accompanied by robust tauopathy. These data suggest that tau misfolding is exacerbated by both newly forming Aβ deposits in younger brain and mature deposits in older brains. Refined use and repurposing of these models provide new tools to explore the intersection of ageing, amyloid and tauopathy and to test interventions to disrupt the amyloid cascade.

Human apolipoprotein E isoforms are differentially sialylated and the sialic acid moiety in ApoE2 attenuates ApoE2-Aβ interaction and Aβ fibrillation

The APOE genotype is the most prominent genetic risk factor for the development of late-onset Alzheimer’'s disease (LOAD); however, the underlying mechanisms remain unclear. In the present study, we found that the sialylation profiles of ApoE protein in the human brain are significantly different among the three isoforms, with ApoE2 exhibiting the most abundant sialic acid modification whereas ApoE4 had the least. We further observed that the sialic acid moiety in ApoE2 significantly affected the interaction between ApoE2 and Aβ peptides. The removal of sialic acid in ApoE2 increased the ApoE2 binding affinity for the Aβ17–24 region of Aβ and promoted Aβ fibrillation. These findings provide a plausible explanation for the well-documented differential roles of ApoE isoforms in Aβ pathogenesis. Specifically, compared to the other two isotypes, the higher expression of sialic acid in ApoE2 may contribute to the less potent interaction between ApoE2 and Aβ and ultimately the slower rate of brain Aβ deposition, a mechanism thought to underlie ApoE2-mediated decreased risk for AD. Future studies are warranted to determine whether the differential sialylation in ApoE isoforms may also contribute to some of their other distinct properties, such as their divergent preferences in associations with lipids and lipoproteins, as well as their potential impact on neuroinflammation through modulation of microglial Siglec activity. Overall, our findings lead to the insight that the sialic acid structure is an important posttranslational modification (PTM) that alters ApoE protein functions with relevance for AD.

Quantifying perivascular space in Alzheimer's disease by MRI relaxometry

AbstractBackgroundThe perivascular space (PVS) is a known key route of glymphatic clearance for the drainage of interstitial fluid and solutes such as soluble amyloid beta (Aβ) from the brain. Perivascular space dilation in aging could indicate abnormal protein accretion, such as Aβ accumulation. Recent studies indicate that dilation of PVS is associated with blocked cerebrospinal fluid (CSF) bulk flow, which is considered as free water. We propose to use MR T2 relaxometry‐based water compartment model for the quantification of free water in brain parenchyma and hence to infer the change of PVS.MethodWe filtered the 22 Aβ positive MCI subjects with three echo T2‐star data and amyloid PET from ADNI database. The three‐echo data was fitted to a two‐water compartment model (CSF and intro‐extracellular water), in which the water compartments were distinguished by the T2 relaxometry time. CSF fraction (CSFF) values were then extracted in the brain region masks generated from FreeSurfer. Mean CSFF for each subject was then calculated. The SUVr of cerebral cortex was used to evaluate brain amyloid load. Linear regression model between Aβ deposition and CSFF was built with age and gender controlled.ResultThe results from ADNI data show that CSFF is linearly related to the Aβ deposition in brain. Fig. 1 presents a map of CSFF and the amyloid PET for the same subject. Fig. 2 shows linear relationship (p<0.05) between CSFF and the SUVr in the cerebral cortex area.ConclusionThe relation between CSFF and amyloid load in brain cortex shows that CSFF could be a potential biomarker for the amyloid clearance. The CSFF map reflects the percentage of free water in total volume at the water molecular level and can sensitively detect subtle PVS change.

Associations between air pollution and biomarkers of Alzheimer's disease in cognitively unimpaired individuals.

Air quality contributes to incidence of Alzheimer's disease (AD) although the underlying neurobiological mechanisms are unclear. This study was aimed to examine the association between air pollution and concentrations of cerebrospinal fluid (CSF) AD biomarkers and amyloid-β (Aβ) deposition. Participants and methods The sample included 156 cognitively unimpaired adults aged 57years (61 at biomarkers assessment) with increased risk of AD from the ALFA+Study. We examined CSF levels of Aβ42, Aβ40, p-Tau, t-Tau, neurofilament light (NfL) and cerebral amyloid load (Centiloid). A Land Use Regression model from 2009 was used to estimate residential exposure to air pollutants including nitrogen dioxide (NO2,) and particulate matter (PM2.5, PM2.5 abs, PM10). This model was considered a surrogate of long-term exposure until time of data collection in 2013-2014. Participants have resided in the same residence for at least the previous 3years. Multiple linear regression models were used to estimate associations between air pollutants and biomarkers. The effect modification by CSF Aβ status and APOE-ε4 carriership was also assessed. A consistent pattern of results indicated that greater exposure to NO2 and PM2.5 absorbance was associated with higher levels of brain Aβ deposition, while greater exposure to PM10 and PM2.5was associated with higher levels of CSF NfL. Most associations were driven by individuals that were Aβ-positive. Although APOE-ε4 status did not significantly modify these associations, the effect of air pollutants exposure on CSF NfL levels was stronger in APOE-ε4 carriers. In a population of cognitively unimpaired adults with increased risk of AD, long-term exposure to air pollution was associated with higher levels in biomarkers of AD pathology. While further research is granted to elucidate the mechanisms involved in such associations, our results reinforce the role of air pollution as an environmental risk factor for AD.

The APP669‐711/Aβ1‐40 ratio as a plasma biomarker specific for the brain Aβ deposition in APP/PS1 mouse

AbstractBackgroundWe have previously identified APP669‐711 (a.k.a. Aβ(‐3)‐40) in human plasma using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS) (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014). Our assay has revealed that the composite biomarker, which is a combination of APP669‐711/Aβ1‐42 ratio and Aβ1‐40/ Aβ1‐42 ratio in human plasma, correlates with amyloid PET status (Nakamura et al., Nature 2018). However, the significance of these peptide ratios in an APP/PS1 mouse model of Alzheimer's disease has been unclear. In this study, we investigated the levels of Aβ‐related peptides including APP669‐711 in plasma samples from the model mouse.MethodWe prepared plasma samples from young (2 months of age) and old (23–25 months of age) APP/PS1 mice expressing both APP bearing the Swedish mutation and PSEN1 harboring ΔE9 mutation, and cultured supernatants of HEK293 cells. Mouse plasma samples and cultured supernatants were measured by IP‐MALDI‐MS.ResultHuman APP669‐711 was detected in cultured supernatant of HEK293 cells overexpressing human wild‐type APP but not human APP with the Swedish mutation. This result indicated that two amino acid substitutions (i.e., Swedish mutation) near the APP669 site inhibited the APP669 cleavage and the production of APP669‐711 from the transgene of APP/PS1 mice. Then we focused on mouse endogenous murine Aβ‐related peptides in the evaluation of plasma biomarker for the amyloid deposition in the brains of APP/PS1 mice. The analysis of APP/PS1 mouse plasma showed that murine APP669‐711/Aβ1‐42 and APP669‐711/Aβ1‐40 ratios were increased in old mice with plaques compared to young mice without them. However, the murine Aβ1‐40/Aβ1‐42 ratio was not changed between old and young mice.ConclusionThese results suggested that the APP669‐711/Aβ1‐42 ratio is a common biomarker for the amyloid plaque pathology in humans and APP/PS1 mice. Also, we revealed the possibility that the APP669‐711/Aβ1‐40 ratio is a biomarker specific for the brain Aβ deposition in APP/PS1 mice. These biomarkers can be useful tools to study lifestyle intervention and drug development for the prevention of amyloid deposition using the model mouse.

Global cognitive dysfunction and β-amyloid neuropathology in late-life and treatment-resistant major depression

AbstractBackgroundCognitive impairment is common in late-life depression, which may increase Alzheimer disease (AD) risk. Therefore, we aimed to investigate whether late-life major depressive disorder (MDD) has worse cognition and increases the characteristic AD neuropathology. Furthermore, we carried out a comparison between treatment-resistant depression (TRD) and non-TRD. We hypothesized that patients with late-life depression and TRD may have increased β-amyloid (Aβ) deposits in brain regions responsible for global cognition.MethodsWe recruited 81 subjects, including 54 MDD patients (27 TRD and 27 non-TRD) and 27 matched healthy controls (HCs). Neurocognitive tasks were examined, including Mini-Mental State Examination and Montreal Cognitive Assessment to detect global cognitive functions. PET with Pittsburgh compound-B and fluorodeoxyglucose were used to capture brain Aβ pathology and glucose use, respectively, in some patients.ResultsMDD patients performed worse in Montreal Cognitive Assessment (p = 0.003) and had more Aβ deposits than HCs across the brain (family-wise error-corrected p < 0.001), with the most significant finding in the left middle frontal gyrus. Significant negative correlations between global cognition and prefrontal Aβ deposits existed in MDD patients, whereas positive correlations were noted in HCs. TRD patients had significantly more deposits in the left-sided brain regions (corrected p < 0.001). The findings were not explained by APOE genotypes. No between-group fluorodeoxyglucose difference was detected.ConclusionsLate-life depression, particularly TRD, had increased brain Aβ deposits and showed vulnerability to Aβ deposits. A detrimental role of Aβ deposits in global cognition in patients with late-onset or non-late-onset MDD supported the theory that late-life MDD could be a risk factor for AD.

Effects of on behavior and blood-brain barrier in Alzheimer's disease mice.

To investigate the effects of on behavior and blood brain barrier (BBB) in Alzheimer's disease mice. Thirty-eight 4-month-old APP/PS1 double transgenic mice were randomly divided into three groups: model group, low-dose group and high-dose group. Saline, and 12 g·kg·d were given to each group by continuous gavage once a day for respectively. The changes in activities of daily live and fear conditioning memory behavior of mice were examined by nesting behavior test and fear conditioning test, respectively. The β-amyloid protein (Aβ) depositions in cortex and hippocampal CA1 area of mice were detected by thioflavin T staining. The CD34 and activities fibrinogen (Fib) immunofluorescence double staining were used to determine the vascular endothelial integrity and BBB exudation. Compared with model mice, activities of daily live were significantly improved in low-dose and high-dose groups (both <0.01), the fear memory ability was significantly increased in high-dose group (<0.01). The amount of Aβ deposition in cortex and hippocampal CA1 decreased significantly in high-dose group, the area ratio decreased significantly; the area ratio of Aβ deposition in hippocampal CA1 region in low-dose group also decreased (all <0.05). The proportions of CD34 positive area of cortex in low and high dose groups increased, the percentage of fibrinogen positive area decreased (all <0.05). The proportion of CD34 positive area in hippocampal CA1 region in high-dose group was significantly increased, the percentage of fibrinogen positive area decreased significantly (both <0.05). especially high-dose can improve the activities of daily live and fear conditioning memory function of APP/PS1 mice, reduce the deposition of Aβ in brain. The mechanism may be related to the reduction of BBB permeability and the protection of the integrity of BBB.

The Function of Aβ in the Healthy Brain: Beta Amyloid as an Antimicrobial Protein

Abstract: There is no question as to whether or not the beta amyloid (Aβ) peptide plays a role in the exacerbation and onset of AD. There are very evident correlations between the volume of Aβ deposition in the AD brain and the severity of the symptoms of AD-typical neurodegeneration. There are certainly many factors involved in the progression of AD, of which the aggregation of Aβ peptides is only one. While many have ruminated on the mechanism by which Aβ serves to impair synaptic function and contribute to neurodegeneration, the role of this protein has yet to be fully uncovered, not just in the AD brain, but in the normally functioning brain as well. Recent research has shed light on the role of Aβ in the normal brain, offering evidence for the fact that beta amyloid functions as an antimicrobial protein, with its primary objective being to serve an immunoresponsive purpose. This text will highlight some of the critical studies on the topic, and illuminate the role that Aβ most likely plays in the functioning of the normal brain, and how this influences its pathological deposition in the AD brain.

Sophocarpine Attenuates Cognitive Impairment and Promotes Neurogenesis in a Mouse Model of Alzheimer’s Disease

Introduction: Alzheimer’s disease (AD), which is characterized by abnormal deposition of amyloid-β (Aβ) plaques and impaired neurogenesis and cognition, still lacks an optimally effective therapeutic agent for its management, and mounting evidence has shown that inflammatory processes are implicated in AD. Sophocarpine has been reported to exert inflammation-regulating effects in various diseases. However, whether sophocarpine can exert anti-neuroinflammatory and neuroprotective effects in AD remains unclear. This study investigated whether sophocarpine could ameliorate the pathological features and potential mechanisms in a mouse AD model. Methods: APP/PS1 mice were treated with sophocarpine for 8 weeks. We quantified the effects of sophocarpine treatment on cognitive performance using a behavioral test. Brain Aβ deposits and neurogenesis were evaluated using immunofluorescence staining. We also assessed the morphology and inflammatory changes induced by sophocarpine administration and its expression in the hippocampus. Results: Administration of sophocarpine significantly alleviated cognitive impairment and reduced neural loss. APP/PS1 mice treated with sophocarpine showed reduced Aβ plaque deposits and enhanced neurogenesis. Sophocarpine markedly decreased the expression of inflammation markers and inhibited microglial activation. Conclusions: Sophocarpine could potentially alleviate cognitive impairment and brain damage in APP/PS1 mice with its neuroprotective effects via modulation of the inflammatory pathway.

In-vitro and in-vivo characterization of CRANAD-2 for multi-spectral optoacoustic tomography and fluorescence imaging of amyloid-beta deposits in Alzheimer mice

The abnormal deposition of fibrillar beta-amyloid (Aβ) deposits in the brain is one of the major histopathological hallmarks of Alzheimer’s disease (AD). Here, we characterized curcumin-derivative CRANAD-2 for multi-spectral optoacoustic tomography and fluorescence imaging of brain Aβ deposits in the arcAβ mouse model of AD cerebral amyloidosis. CRANAD-2 showed a specific and quantitative detection of Aβ fibrils in vitro, even in complex mixtures, and it is capable of distinguishing between monomeric and fibrillar forms of Aβ. In vivo epi-fluorescence microscopy and optoacoustic tomography after intravenous CRANAD-2 administration demonstrated higher cortical retention in arcAβ compared to non-transgenic littermate mice. Immunohistochemistry showed co-localization of CRANAD-2 and Aβ deposits in arcAβ mouse brain sections, thus verifying the specificity of the probe. In conclusion, we demonstrate suitability of CRANAD-2 for optical detection of Aβ deposits in animal models of AD pathology, which facilitates mechanistic studies and the monitoring of putative treatments targeting Aβ deposits.

Detecting amyloid positivity in early Alzheimer's disease using combinations of plasma Aβ42/Aβ40 and p-tau.

We studied usefulness of combining blood amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p-tau)217, and neurofilament light (NfL) to detect abnormal brain Aβ deposition in different stages of early Alzheimer's disease (AD). Plasma biomarkers were measured using mass spectrometry (Aβ42/Aβ40) and immunoassays (p-tau217 and NfL) in cognitively unimpaired individuals (CU, N=591) and patients with mild cognitive impairment (MCI, N=304) from two independent cohorts (BioFINDER-1, BioFINDER-2). In CU, a combination of plasma Aβ42/Aβ40 and p-tau217 detected abnormal brain Aβ status with area under the curve (AUC) of 0.83 to 0.86. In MCI, the models including p-tau217 alone or Aβ42/Aβ40 and p-tau217 had similar AUCs (0.86-0.88); however, the latter showed improved model fit. The models were implemented in an online application providing individualized risk assessments (https://brainapps.shinyapps.io/PredictABplasma/). A combination of plasma Aβ42/Aβ40 and p-tau217 discriminated Aβ status with relatively high accuracy, whereas p-tau217 showed strongest associations with Aβ pathology in MCI but not in CU.

Neuronal loss and microgliosis are restricted to the core of Aβ deposits in mouse models of Alzheimer's disease.

Amyloid‐β (Aβ) deposits, pathologic tau, and neurodegeneration are major pathological hallmarks of Alzheimer's disease (AD). The relationship between neuronal loss and Aβ deposits is one of the fundamental questions in the pathogenesis of AD. However, this relationship is controversial. One main reason for the conflicting results may be the confounding effects of pathologic tau, which often coexists with Aβ deposits in the brains of AD patients. To clarify the relationship between neuronal loss and Aβ deposits, mouse models of AD, which develop abundant Aβ deposits in the aged brain without pathologic tau, were used to examine the co‐localization of NeuN‐positive neurons, NF‐H‐positive axons, MBP‐positive myelin sheaths, and Aβ deposits. Neuronal loss, as measured by decreased staining of the neuronal cell body, axon, and myelin sheath, as well as the IBA‐1‐positive microglia, was significantly increased in the core area of cerebral Aβ deposits, but not in adjacent areas. Furthermore, neuronal loss in the core area of cerebral Aβ deposits was correlated with Aβ deposit size. These results clearly indicate that neuronal loss is restricted to the core of Aβ deposits, and this restricted loss probably occurs because the Aβ deposit attracts microglia, which cluster in the core area where Aβ toxicity and neuroinflammation toxicity are restrained. These findings may contribute to our understanding of the relationship between neuronal loss and Aβ deposits in the absence of pathologic tau.

Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer's disease.

Amyloid-β (Aβ) accumulation in the brain is a pivotal event in the pathogenesis of Alzheimer's disease (AD), and its clearance from the brain is impaired in sporadic AD. Previous studies suggest that approximately half of the Aβ produced in the brain is cleared by transport into the periphery. However, the mechanism and pathophysiological significance of peripheral Aβ clearance remain largely unknown. The kidney is thought to be responsible for Aβ clearance, but direct evidence is lacking. In this study, we investigated the impact of unilateral nephrectomy on the dynamic changes in Aβ in the blood and brain in both humans and animals and on behavioural deficits and AD pathologies in animals. Furthermore, the therapeutic effects of the diuretic furosemide on Aβ clearance via the kidney were assessed. We detected Aβ in the kidneys and urine of both humans and animals and found that the Aβ level in the blood of the renal artery was higher than that in the blood of the renal vein. Unilateral nephrectomy increased brain Aβ deposition; aggravated AD pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, and neuronal loss; and aggravated cognitive deficits in APP/PS1 mice. In addition, chronic furosemide treatment reduced blood and brain Aβ levels and attenuated AD pathologies and cognitive deficits in APP/PS1 mice. Our findings demonstrate that the kidney physiologically clears Aβ from the blood, suggesting that facilitation of Aβ clearance via the kidney represents a novel potential therapeutic approach for AD.

DJ-1 affects oxidative stress and pyroptosis in hippocampal neurons of Alzheimer's disease mouse model by regulating the Nrf2 pathway.

Studies have confirmed that DJ-1 is associated with diseases associated with the nervous system, including Alzheimer's disease (AD). However, the role of DJ-1 in the pathogenesis of AD has not been clarified. To investigate the effect of DJ-1 on brain tissue damage and cognitive function in AD mice and its possible mechanism, 5XFAD transgenic mice were used as AD model mice and DJ-1 in the brain was overexpressed by transfection of a lentiviral containing a specific targeting DJ-1 gene into the bilateral hippocampus of mice. Following lentivirus infection, the Morris water maze test was performed to assess the cognitive function of the mice. When the behavioral evaluation was completed, the brain tissue of the mouse was examined. Pathological changes were observed by hematoxylin-eosin staining. The levels of relevant indicators were analyzed by reverse transcription-quantitative PCR, ELISA and western blotting. Bilateral hippocampal injection of a lentivirus containing DJ-1 significantly increased the expression of DJ-1 in the hippocampus of 5XFAD transgenic mice. Overexpression of DJ-1 in the brain could ameliorate brain tissue damage, β-amyloid protein (Aβ) deposition and cognitive function in 5XFAD mice. Compared with the sham group, the reactive oxygen species activity and malondialdehyde content in the brain tissue of DJ-1 overexpressing 5XFAD mice were significantly decreased, while the superoxide dismutase activity was significantly increased (P<0.05). In addition, DJ-1 overexpression decreased the expression of caspase-1 and the levels of interleukin (IL) 1β and IL-18 in the hippocampus while ameliorating the death of hippocampal neurons in 5XFAD mice and without affecting the expression of caspase-3. Overexpression of DJ-1 resulted in a significant decrease in nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in the cytoplasmic while significantly increasing the expression of Nrf2 in the nucleus. Simultaneously, DJ-1 overexpression in the brain inhibited the activation of nanoparticles activate the NLR pyrin domain containing 3 inflammatory bodies in brain tissue. Overexpression of DJ-1 in the brain could repair brain tissue damage, Aβ deposition and cognitive function in 5XFAD mice, and its mechanism may be associated with an inhibition of oxidative stress and neuronal pyroptosis by regulating the Nrf2 signaling pathway.

Sleep Disturbance is Associated With Higher Plasma Aβ Levels in Cognitively Normal Adults-A Population-Based Cross-Sectional Study.

Objective: Growing evidence suggests that sleep disturbance is a risk factor for Alzheimer's disease (AD). Amyloid-β (Aβ) deposition in the brain is a main pathophysiology of AD. Considering that peripheral Aβ level is associated with brain Aβ deposition, the present study investigated the relationship between sleep disturbance and plasma Aβ levels.Methods: This is a population-based cross-sectional study. A total of 1,459 participants from a village in the suburbs of Xi'an, China, were enrolled from January 3, 2017 to March 26, 2017. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and a PSQI score of <5 points was considered as good sleep quality and a PSQI score of >10 points as poor sleep quality. Cognitive function was assessed with the Mini-Mental State Examination (MMSE). Fasting venous blood was taken in the morning, and the plasma Aβ levels were measured using ELISA. The relationships between plasma Aβ levels and sleep quality were analyzed using multiple linear regression.Results: Among the participants, 231 had poor sleep quality (15.83%). The log-transformed Aβ40 level had significant differences among the different sleep groups (F = 3.216, p = 0.040). The log-transformed Aβ40 level was higher in the poor sleep quality group than that in the general sleep quality group [87.17 (73.42, 107.34) vs. 89.69 (74.81, 125.79) pg/ml, p = 0.016]. In bivariate analysis, sleep quality was negatively associated with the log-transformed plasma Aβ40 level (β = −0.025, p = 0.011).Conclusion: In the community population, poorer sleep quality is associated with a higher plasma Aβ40 level. This indicated that sleep disturbance might also involve in dysfunction of peripheral Aβ clearance.