Aβ Metabolism Research Articles

Discrepant modulating effects of dietary docosahexaenoic acid on cerebral lipids, fatty acid transporter expression and soluble beta-amyloid levels in ApoE-/- and C57BL/6J mice.

The study was designed to explore the role of apolipoprotein E (ApoE) deficiency concomitant with dietary docosahexaenoic acid (DHA) treatment on brain β-amyloid (Aβ) and lipid levels. A 5-month dietary DHA intervention was conducted in ApoE-deficient (ApoE-/- ) mice and wild-type C57BL/6J (C57 wt) mice. The Morris water maze test was performed to assess the behaviour of the animals. The cortical contents of soluble Aβ1-40 and Aβ1-42 were detected by enzyme-linked immunosorbent assay (ELISA). Cortical fatty acid levels were detected by gas chromatography. Gene and protein expression of molecules associated with cerebral Aβ and lipid metabolism were measured using real-time polymerase chain reaction (PCR), Western blot and histological methods. DHA treatment increased the content of cortical DHA and n-3 polyunsaturated fatty acids (n-3 PUFAs) but decreased the ratio of n-6/n-3 PUFAs in ApoE-/- mice; whereas the content of cortical DHA and n-3 PUFAs in C57 wt mice remained unchanged after DHA treatment. Cerebral Fabp5 and Cd36 gene expression were significantly downregulated in DHA-fed C57 wt mice; cerebral Cd36 and Scarb1 gene expression were significantly upregulated, whereas Fabp5 gene expression was downregulated in DHA-fed ApoE-/- mice. In comparison with C57 wt mice, the content of cortical soluble Aβ1-42 , total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) increased, whereas the level of high-density lipoprotein cholesterol (HDL-C) decreased in ApoE-/- mice. Interestingly, these differences were significantly reversed by DHA dietary treatment. DHA intervention has discrepant impacts on cerebral lipids, fatty acid transporter expression and soluble Aβ levels in ApoE-/- and C57 wt mice, suggesting the modifying role of ApoE status on the responses of cerebral lipids and Aβ metabolism to DHA treatment.

P75 neurotrophin receptor as a therapeutic target for drug development to treat neurological diseases.

The interaction of neurotrophins with their receptors is involved in the pathogenesis and progression of various neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury and acute and chronic cerebral damage. The p75 neurotrophin receptor (p75NTR) plays a pivotal role in the development of neurological dysfunctions as a result of its high expression, abnormal processing and signalling. Therefore, p75NTR represents as a vital therapeutic target for the treatment of neurodegeneration, neuropsychiatric disorders and cerebrovascular insufficiency. This review summarizes the current research progress on the p75NTR signalling in neurological deficits. We also summarize the present therapeutic approaches by genetically and pharmacologically targeting p75NTR for the attenuation of pathological changes. Based on the evolving knowledge, the role of p75NTR in the regulation of tau hyperphosphorylation, Aβ metabolism, the degeneration of motor neurons and dopaminergic neurons has been discussed. Its position as a biomarker to evaluate the severity of diseases and as a druggable target for drug development has also been elucidated. Several prototype small molecule compounds were introduced to be crucial in neuronal survival and functional recovery via targeting p75NTR. These small molecule compounds represent desirable agents in attenuating neurodegeneration and cell death as they abolish activation-induced neurotoxicity of neurotrophins via modulating p75NTR signalling. More comprehensive and in-depth investigations on p75NTR-based drug development are required to shed light on effective treatment of numerous neurological disorders.

Screening for Genetic Mutations Associated with Early-Onset Alzheimer's Disease in Han Chinese.

Early-onset Alzheimer's disease (EOAD) is highly influenced by genetic factors. Numerous mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2) have been identified for EOAD, but they can only account for a small proportion of EOAD cases. This study aimed to screen genetic mutations and variants associated with EOAD among Han Chinese adults. This study included 34 patients with EOAD and 26 controls from a population-based study and neurological ward. We first sequenced mutations in APP/PSENs and then performed whole-exome sequencing in the remaining patients with negative mutations in APP/PSENs to screen for additional potential genetic variants. Among patients who were negative in genetic screening tests, we further evaluated the risk burden of genes related to the Aβ metabolism-centered network to search for other probable causes of EOAD. We identified 7 functional variants in APP/PSENs in 8 patients, including 1 APP mutation (p. Val715Met), 3 PSEN1 mutations (p. Phe177Ser; p. Arg377Met; p. Ile416Thr), and 3 PSEN2 mutations (p. Glu24Lys; p. Gly34Ser; p. Met239Thr). Of the remaining 26 EOAD cases without mutations in APP/PSENs, the proportion of carrying rare variants of genes involved in Aβ and APP metabolism was significantly higher than that of controls (84.6% vs. 73.1%, P=0.042). Thirty-one risk genes with 47 variants were identified in 22 patients. However, in 26 normal subjects, only 20 risk genes with 29 variants were identified in 19 subjects. Our findings demonstrate the role of APP/PSENs mutations in EOAD, identifying a new PSEN2 missense mutation, and further offer valuable insights into the potential genetic mechanisms of EOAD without APP/PSENs mutations among Han Chinese.

Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies.

Amyloid-β (Aβ) has long been considered as one of the most important pathogenic factors in Alzheimer’s disease (AD), but the specific pathogenic mechanism of Aβ is still not completely understood. In recent years, the development of structural biology technology has led to new understandings about Aβ molecular structures, Aβ generation and clearance from the brain and peripheral tissues, and its pathological toxicity. The purpose of the review is to discuss Aβ metabolism and toxicity, and the therapeutic strategy of AD based on the latest progress in molecular structures of Aβ. The Aβ structure at the atomic level has been analyzed, which provides a new and refined perspective to comprehend the role of Aβ in AD and to formulate therapeutic strategies of AD.

Tau as a biomarker of cognitive impairment and neuropsychiatric symptom in Alzheimer's disease.

The A/T/N research framework has been proposed for the diagnosis and prognosis of Alzheimer's disease (AD). However, the spatial distribution of ATN biomarkers and their relationship with cognitive impairment and neuropsychiatric symptoms (NPS) need further clarification in patients with AD. We scanned 83AD patients and 38 cognitively normal controls who independently completed the mini-mental state examination and Neuropsychiatric Inventory scales. Tau, Aβ, and hypometabolism spatial patterns were characterized using Statistical Parametric Mapping together with [18F]flortaucipir, [18F]florbetapir, and [18F]FDG positron emission tomography. Piecewise linear regression, two-sample t-tests, and support vector machine algorithms were used to explore the relationship between tau, Aβ, and hypometabolism and cognition, NPS, and AD diagnosis. The results showed that regions with tau deposition are region-specific and mainly occurred in inferior temporal lobes in AD, which extensively overlaps with the hypometabolic regions. While the deposition regions of Aβ were unique and the regions affected by hypometabolism were widely distributed. Unlike Aβ, tau and hypometabolism build up monotonically with increasing cognitive impairment in the late stages of AD. In addition, NPS in AD were associated with tau deposition closely, followed by hypometabolism, but not with Aβ. Finally, hypometabolism and tau had higher accuracy in differentiating the AD patients from controls (accuracy=0.88, accuracy=0.85) than Aβ (accuracy=0.81), and the combined three were the highest (accuracy=0.95). These findings suggest tau pathology is superior over Aβ and glucose metabolism to identify cognitive impairment and NPS. Its results support tau accumulation can be used as a biomarker of clinical impairment in AD.

Clinical course and serum amyloid β levels in elderly patients with major depressive disorder

BackgroundDepression is known to be a risk factor for Alzheimer's disease (AD). Changes in amyloid β protein (Aβ) metabolism have been speculated as a factor contributing to the transition from depression to AD. The aim of this study is to reveal the time course and state-dependency of Aβ metabolism. MethodsSerum Aβ levels in 277 elderly (≥60 years) patients with depression (both early- and late-onset) were measured at admission, immediately after remission, and 1 year after remission, and compared them with 178 healthy subjects. ResultsThe analysis revealed decreased Aβ42 levels and increased Aβ42/40 ratios in elderly patients with depression at admission compared with healthy subjects. These changes in the acute phase of depression were not normalized immediately after remission; however, they recovered to healthy levels 1 year after remission. LimitationsThere is a possibility that the results may be influenced by antidepressants. ConclusionsThese results suggest that altered Aβ metabolism caused by depression may ameliorate, although after a lengthy period of time after remission. Our findings also suggest that the AD-related pathological changes caused or increased by depression can be reduced by maintaining remission for an extended period of time.

The Role of Mesenchymal Stem Cells in Regulating Astrocytes-Related Synapse Dysfunction in Early Alzheimer's Disease.

Alzheimer’s disease (AD), a neurodegenerative disease, is characterized by the presence of extracellular amyloid-β (Aβ) aggregates and intracellular neurofibrillary tangles formed by hyperphosphorylated tau as pathological features and the cognitive decline as main clinical features. An important cellular correlation of cognitive decline in AD is synapse loss. Soluble Aβ oligomer has been proposed to be a crucial early event leading to synapse dysfunction in AD. Astrocytes are crucial for synaptic formation and function, and defects in astrocytic activation and function have been suggested in the pathogenesis of AD. Astrocytes may contribute to synapse dysfunction at an early stage of AD by participating in Aβ metabolism, brain inflammatory response, and synaptic regulation. While mesenchymal stem cells can inhibit astrogliosis, and promote non-reactive astrocytes. They can also induce direct regeneration of neurons and synapses. This review describes the role of mesenchymal stem cells and underlying mechanisms in regulating astrocytes-related Aβ metabolism, neuroinflammation, and synapse dysfunction in early AD, exploring the open questions in this field.

Small RNA Sequencing in the Tg4-42 Mouse Model Suggests the Involvement of snoRNAs in the Etiology of Alzheimer's Disease.

The Tg4-42 mouse model for sporadic Alzheimer's disease (AD) has unique features, as the neuronal expression of wild type N-truncated Aβ4-42 induces an AD-typical neurological phenotype in the absence of plaques. It is one of the few models developing neuron death in the CA1 region of the hippocampus. As such, it could serve as a powerful tool for preclinical drug testing and identification of the underlying molecular pathways that drive the pathology of AD. The aim of this study was to use a differential co-expression analysis approach for analyzing a small RNA sequencing dataset from a well-established murine model in order to identify potentially new players in the etiology of AD. To investigate small nucleolar RNAs in the hippocampus of Tg4-42 mice, we used RNA-Seq data from this particular tissue and, instead of analyzing the data at single gene level, employed differential co-expression analysis, which takes the comparison to gene pair level and thus affords a new angle to the interpretation of these data. We identified two clusters of differentially correlated small RNAs, including Snord55, Snord57, Snord49a, Snord12, Snord38a, Snord99, Snord87, Mir1981, Mir106b, Mir30d, Mir598, and Mir99b. Interestingly, some of them have been reported to be functionally relevant in AD pathogenesis, as AD biomarkers, regulating tau phosphorylation, TGF-β receptor function or Aβ metabolism. The majority of snoRNAs for which our results suggest a potential role in the etiology of AD were so far not conspicuously implicated in the context of AD pathogenesis and could thus point towards interesting new avenues of research in this field.

Amentoflavone Promotes Cellular Uptake and Degradation of Amyloid-Beta in Neuronal Cells

Deposition of fibrillar forms of amyloid β-protein (Aβ) is commonly found in patients with Alzheimer’s disease (AD) associated with cognitive decline. Impaired clearance of Aβ species is thought to be a major cause of late-onset sporadic AD. Aβ secreted into the extracellular milieu can be cleared from the brain through multiple pathways, including cellular uptake in neuronal and non-neuronal cells. Recent studies have showed that the naturally-occurring polyphenol amentoflavone (AMF) exerts anti-amyloidogenic effects. However, its effects on metabolism and cellular clearance of Aβ remain to be tested. In the present study, we demonstrated that AMF significantly increased the cellular uptake of both Aβ1-40 and Aβ1-42, but not inverted Aβ42-1 in mouse neuronal N2a cells. Though AMF promoted internalization of cytotoxic Aβ1-42, it significantly reduced cell death in our assay condition. Our data further revealed that the internalized Aβ is translocated to lysosomes and undergoes enzymatic degradation. The saturable kinetic of Aβ uptake and our pharmacologic experiments showed the involvement of receptor-mediated endocytosis, in part, through the class A scavenger receptors as a possible mechanism of action of AMF. Taken together, our findings indicate that AMF can lower the levels of extracellular Aβ by increasing their cellular uptake and clearance, suggesting the therapeutic potential of AMF for the treatment of AD.

The neuroprotective effects of oxygen therapy in Alzheimer’s disease: a narrative review

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Transcranial Direct Current Stimulation Alleviates Neurovascular Unit Dysfunction in Mice With Preclinical Alzheimer's Disease.

Neurons, glial cells and blood vessels are collectively referred to as the neurovascular unit (NVU). In the Alzheimer’s disease (AD) brain, the main components of the NVU undergo pathological changes. Transcranial direct current stimulation (tDCS) can protect neurons, induce changes in glial cells, regulate cerebral blood flow, and exert long-term neuroprotection. However, the mechanism by which tDCS improves NVU function is unclear. In this study, we explored the effect of tDCS on the NVU in mice with preclinical AD and the related mechanisms. 10 sessions of tDCS were given to six-month-old male APP/PS1 mice in the preclinical stage. The model group, sham stimulation group, and control group were made up of APP/PS1 mice and C57 mice of the same age. All mice were histologically evaluated two months after receiving tDCS. Protein content was measured using Western blotting and an enzyme-linked immunosorbent assay (ELISA). The link between glial cells and blood vessels was studied using immunofluorescence staining and lectin staining. The results showed that tDCS affected the metabolism of Aβ; the levels of Aβ, amyloid precursor protein (APP) and BACE1 were significantly reduced, and the levels of ADAM10 were significantly increased in the frontal cortex and hippocampus in the stimulation group. In the stimulation group, tDCS reduced the protein levels of Iba1 and GFAP and increased the protein levels of NeuN, LRP1 and PDGRFβ. This suggests that tDCS can improve NVU function in APP/PS1 mice in the preclinical stage. Increased blood vessel density and blood vessel length, decreased IgG extravasation, and increased the protein levels of occludin and coverage of astrocyte foot processes with blood vessels suggested that tDCS had a protective effect on the blood-brain barrier. Furthermore, the increased numbers of Vimentin, S100 expression and blood vessels (lectin-positive) around Aβ indicated that the effect of tDCS was mediated by astrocytes and blood vessels. There was no significant difference in these parameters between the model group and the sham stimulation group. In conclusion, our results show that tDCS can improve NVU function in APP/PS1 mice in the preclinical stage, providing further support for the use of tDCS as a treatment for AD.

KIBRA regulates amyloid β metabolism by controlling extracellular vesicles secretion.

SummaryBackgroundPrevious research has revealed that KIBRA controls secretion of extracellular vesicles (EVs) by inhibiting the proteasomal degradation of Rab27a and EVs play an important role in amyloid β (Aβ) metabolism and transmission during Alzheimer's disease (AD) pathogenesis. Here, we further test the hypothesis that KIBRA regulates Aβ metabolism via the endosomal-lysosomal system.MethodsWe generated KIBRA knockout mice on a 5XFAD background and KIBRA knockdown cells in murine HT22 cells with stably overexpressing APP. Various forms of Aβ and quantification of EVs were analyzed by biochemical methods and nanoparticle tracking analysis, respectively. Multivesicular bodies (MVBs) were visualized by electron microscopy and confocal fluorescent microscopy. In a population-based cohort (n = 1419), KIBRA genotypes and plasma Aβ levels were analyzed using multiple-PCR amplification and Simoa, respectively.FindingsMultiple forms of Aβ were dramatically attenuated in KIBRA knockout mouse brain, including monomers, oligomers, and extracellular deposition, but KIBRA knockout had no effect on intraneuronal APP C-terminal fragment β (APP-CTFβ)/Aβ levels. KIBRA depletion also decreased APP-CTFβ/Aβ-associated EVs secretion and subsequently enhanced MVBs number. Furthermore, we found that excessive accumulation of MVBs harboring APP-CTFβ/Aβ promoted the MVBs-lysosome fusion for degradation and inhibition of lysosomal function rescued secretion of APP-CTFβ/Aβ-associated EVs. More importantly, whole exon sequencing of KIBRA in a large population-based cohort identified the association of KIBRA rs28421695 polymorphism with plasma Aβ levels.InterpretationThese results demonstrate that KIBRA regulates Aβ metabolism via controlling the secretion of APP-CTFβ/Aβ-associated EVs.FundingNational Key R&D Program of China, and National Natural Science Foundation of China.

Aβ profiles generated by Alzheimer’s disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset

Familial Alzheimer’s disease (FAD), caused by mutations in Presenilin (PSEN1/2) and Amyloid Precursor Protein (APP) genes, is associated with an early age at onset (AAO) of symptoms. AAO is relatively consistent within families and between carriers of the same mutations, but differs markedly between individuals carrying different mutations. Gaining a mechanistic understanding of why certain mutations manifest several decades earlier than others is extremely important in elucidating the foundations of pathogenesis and AAO. Pathogenic mutations affect the protease (PSEN/γ-secretase) and the substrate (APP) that generate amyloid β (Aβ) peptides. Altered Aβ metabolism has long been associated with AD pathogenesis, with absolute or relative increases in Aβ42 levels most commonly implicated in the disease development. However, analyses addressing the relationships between these Aβ42 increments and AAO are inconsistent. Here, we investigated this central aspect of AD pathophysiology via comprehensive analysis of 25 FAD-linked Aβ profiles. Hypothesis- and data-driven approaches demonstrate linear correlations between mutation-driven alterations in Aβ profiles and AAO. In addition, our studies show that the Aβ (37 + 38 + 40) / (42 + 43) ratio offers predictive value in the assessment of ‘unclear’ PSEN1 variants. Of note, the analysis of PSEN1 variants presenting additionally with spastic paraparesis, indicates that a different mechanism underlies the aetiology of this distinct clinical phenotype. This study thus delivers valuable assays for fundamental, clinical and genetic research as well as supports therapeutic interventions aimed at shifting Aβ profiles towards shorter Aβ peptides.

Recent Advances in the Modeling of Alzheimer's Disease.

Since 1995, more than 100 transgenic (Tg) mouse models of Alzheimer’s disease (AD) have been generated in which mutant amyloid precursor protein (APP) or APP/presenilin 1 (PS1) cDNA is overexpressed (1st generation models). Although many of these models successfully recapitulate major pathological hallmarks of the disease such as amyloid β peptide (Aβ) deposition and neuroinflammation, they have suffered from artificial phenotypes in the form of overproduced or mislocalized APP/PS1 and their functional fragments, as well as calpastatin deficiency-induced early lethality, calpain activation, neuronal cell death without tau pathology, endoplasmic reticulum stresses, and inflammasome involvement. Such artifacts bring two important uncertainties into play, these being (1) why the artifacts arise, and (2) how they affect the interpretation of experimental results. In addition, destruction of endogenous gene loci in some Tg lines by transgenes has been reported. To overcome these concerns, single App knock-in mouse models harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL–G–F and AppNL–F mice) were developed (2nd generation models). While these models are interesting given that they exhibit Aβ pathology, neuroinflammation, and cognitive impairment in an age-dependent manner, the model with the Artic mutation, which exhibits an extensive pathology as early as 6 months of age, is not suitable for investigating Aβ metabolism and clearance because the Aβ in this model is resistant to proteolytic degradation and is therefore prone to aggregation. Moreover, it cannot be used for preclinical immunotherapy studies owing to the discrete affinity it shows for anti-Aβ antibodies. The weakness of the latter model (without the Arctic mutation) is that the pathology may require up to 18 months before it becomes sufficiently apparent for experimental investigation. Nevertheless, this model was successfully applied to modulating Aβ pathology by genome editing, to revealing the differential roles of neprilysin and insulin-degrading enzyme in Aβ metabolism, and to identifying somatostatin receptor subtypes involved in Aβ degradation by neprilysin. In addition to discussing these issues, we also provide here a technical guide for the application of App knock-in mice to AD research. Subsequently, a new double knock-in line carrying the AppNL–F and Psen1P117L/WT mutations was generated, the pathogenic effect of which was found to be synergistic. A characteristic of this 3rd generation model is that it exhibits more cored plaque pathology and neuroinflammation than the AppNL–G–F line, and thus is more suitable for preclinical studies of disease-modifying medications targeting Aβ. Furthermore, a derivative AppG–F line devoid of Swedish mutations which can be utilized for preclinical studies of β-secretase modifier(s) was recently created. In addition, we introduce a new model of cerebral amyloid angiopathy that may be useful for analyzing amyloid-related imaging abnormalities that can be caused by anti-Aβ immunotherapy. Use of the App knock-in mice also led to identification of the α-endosulfine-KATP channel pathway as components of the somatostatin-evoked physiological mechanisms that reduce Aβ deposition via the activation of neprilysin. Such advances have provided new insights for the prevention and treatment of preclinical AD. Because tau pathology plays an essential role in AD pathogenesis, knock-in mice with human tau wherein the entire murine Mapt gene has been humanized were generated. Using these mice, the carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) was discovered as a mediator linking tau pathology to neurodegeneration and showed that tau humanization promoted pathological tau propagation. Finally, we describe and discuss the current status of mutant human tau knock-in mice and a non-human primate model of AD that we have successfully created.

Circadian control of heparan sulfate levels times phagocytosis of amyloid beta aggregates.

Alzheimer’s Disease (AD) is a neuroinflammatory disease characterized partly by the inability to clear, and subsequent build-up, of amyloid-beta (Aβ). AD has a bi-directional relationship with circadian disruption (CD) with sleep disturbances starting years before disease onset. However, the molecular mechanism underlying the relationship of CD and AD has not been elucidated. Myeloid-based phagocytosis, a key component in the metabolism of Aβ, is circadianly-regulated, presenting a potential link between CD and AD. In this work, we revealed that the phagocytosis of Aβ42 undergoes a daily circadian oscillation. We found the circadian timing of global heparan sulfate proteoglycan (HSPG) biosynthesis was the molecular timer for the clock-controlled phagocytosis of Aβ and that both HSPG binding and aggregation may play a role in this oscillation. These data highlight that circadian regulation in immune cells may play a role in the intricate relationship between the circadian clock and AD.

Chronic cerebral hypoperfusion and blood-brain barrier disruption in uninjured brain areas of rhesus monkeys subjected to transient ischemic stroke

Blood-brain barrier (BBB) disruption is a pivotal pathophysiological process in ischemic stroke. Although temporal changes in BBB permeability during the acute phase have been widely studied, little is known about the chronic phase of cerebrovascular changes that may have a large impact on the long-term outcome. Therefore, this study was aimed to measure cerebral vascular abnormalities using CT perfusion in nine rhesus monkeys subjected to transient middle cerebral artery occlusion (tMCAO) for ≥1 year (MCAO-1Y+). The level of cerebral perfusion demonstrated by mean transit time was significantly higher in the ipsilateral caudate nucleus, white matter, thalamus, hippocampus, and contralateral thalamus in MCAO-1Y+ compared with the other nine age-matched control monkeys. The increase in BBB permeability measured through the permeability surface was found in the same ten regions of interest ipsilaterally and contralaterally. We also found decreased levels of Aβ 42/40 ratio in the cerebrospinal fluid (CSF), suggesting a potential link between post-MCAO cognitive decline and Aβ metabolism. Overall, we demonstrated significant cerebral hypoperfusion, BBB disruption, and CSF Aβ decrease during the rehabilitation stage of ischemic stroke in a non-human primate model. Future studies are needed to elucidate the cause-effect relationship between cerebrovascular disruptions and long-term neurological deficits.

Tau proteins in blood as biomarkers of Alzheimer's disease and other proteinopathies.

Alzheimer's disease (AD), the most common age-dependent neurodegenerative disorder, is characterized neuropathologically by extracellular Aβ plaques and intracellular tau neurofibrillary tangles. While in AD tau pathology probably follows early alterations in Aβ metabolism, it develops independently in the so-called primary tauopathies, the main form being frontotemporal lobar degeneration with tau pathology. Tau pathology in AD brain is reflected in the cerebrospinal fluid (CSF) by elevated levels of the two AD tau biomarkers total and phosphorylated tau, which are now used for routine diagnostic purposes. On the contrary, no established neurochemical biomarkers exist for tau pathology in primary tauopathies. Thanks to recent technological advances, total and phosphorylated tau can now be quantified also on peripheral blood, and accumulating evidence shows that measurement of plasma phosphorylated tau species (P-tau181, P-tau217, and P-tau231) has high performances in discriminating AD patients from cognitively unimpaired subjects but also from patients with other dementias. Moreover, plasma P-tau levels are associated with tracer uptake on tau- and amyloid-PET as well as with brain atrophy, cognitive measures and longitudinal changes of these parameters. These features, together with the low invasiveness, scalability, and ease of longitudinal sampling, which differentiate plasma P-tau species from their CSF counterparts, make these proteins promising peripheral biomarkers for AD in both research and clinical setting. This review discusses the recent developments in the field of plasma tau proteins as diagnostic, pathophysiological and prognostic biomarkers of Alzheimer's disease; additional findings from the fields of genetic forms of AD and of non-AD proteinopathies are also summarized.

A direct interaction between RhoGDIα/Tau alleviates hyperphosphorylation of Tau in Alzheimer's disease and vascular dementia.

RhoGDIα is an inhibitor of RhoGDP dissociation that involves in Aβ metabolism and NFTs production in Alzheimer's disease (AD) by regulating of RhoGTP enzyme activity. Our previous research revealed that RhoGDIα, as the target of Polygala saponin (Sen), might alleviate apoptosis of the nerve cells caused by hypoxia/reoxygenation (H/R). To further clarify the role of RhoGDIα in the generation of NFTs, we explored the relationship between RhoGDIα and Tau. We found out that RhoGDIα and Tau can bind with each other and interact by using coimmunoprecipitation (Co-IP) and GST pulldown methods in vitro. This RhoGDIα-Tau partnership was further verified by using immunofluorescence colocalization and fluorescence resonance energy transfer (FRET) approaches in PC12 cells. Using the RNA interference (RNAi) technique, we found that the RhoGDIα may be involved in an upstream signaling pathway for Tau. Subsequently, in Aβ25-35- and H/R-induced PC12 cells, forced expression of RhoGDIα via cDNA plasmid transfection was found to reduce the hyperphosphorylation of Tau, augment the expression of bcl-2 protein, and inhibit the expression of Bax protein (reducing the Bax/bcl-2 ratio) and the activity of caspase-3. In mouse AD and VaD models, forced expression of RhoGDIα via injection of a viral vector (pAAV-EGFP-RhoGDIα) into the lateral ventricle of the brain alleviated the pathological symptoms of AD and VaD. Finally, GST pulldown confirmed that the binding sites on RhoGDIα for Tau were located in the range of the ΔC33 fragment (aa 1-33). These results indicate that RhoGDIα is involved in the phosphorylation of Tau and apoptosis in AD and VaD. Overexpression of RhoGDIα can inhibit the generation of NFTs and delay the progress of these two types of dementia.

Association and interaction of TOMM40 and PVRL2 with plasma amyloid-β and Alzheimer's disease among Chinese older adults: a population-based study

Genetic studies have identified Alzheimer's disease (AD)-associated SNPs in TOMM40 and PVRL2 genes, but the underlying mechanisms remain unknown. We examined their associations and interactions with AD risk and plasma biomarkers among Chinese older adults. This population-based study included 4876 participants. TOMM40(rs2075650) and PVRL2(rs6859) polymorphisms were detected using multiple-polymerase chain reaction amplification. Plasma Aβ40, Aβ42, and t-tau concentrations were measured using SIMOA in a subsample (n = 1257). AD was diagnosed following the international criteria. Data were analyzed using multiple logistic and general linear models. AD was diagnosed in 182 participants. The multiadjusted odds ratio of AD was 6.24 (95% CI 1.73–22.48) for TOMM40GG, 1.47 (0.89–2.42) for PVRL2AA, and 12.87 (3.97–41.73) for having both risk alleles (Pinteraction = 0.0003). Among APOEε3/ε3 carriers, the multiadjusted odds ratio of AD associated with TOMM40AG was 2.90(1.15–7.31). In biomarker subsample, TOMM40GG was significantly associated with lower plasma Aβ42 and the Aβ42-to-Aβ40 ratio (p < 0.05). TOMM40 genotype is differentially associated with AD risk depending on APOE genotype. TOMM40 and PVRL2 genes could interact to substantially increase AD risk, possibly through influencing Aβ metabolism.

Alzheimer’s disease susceptibility locus in CD2AP is associated with increased cerebrospinal fluid tau levels in mild cognitive impairment

IntroductionRs9296559 within CD2-associated protein (CD2AP) has been identified as a susceptibility locus for Alzheimer’s disease (AD). Recent studies indicated that CD2AP functioned as a regulator of endocytic trafficking to modulate the β-amyloid (Aβ) generation in neurons. Moreover, knockdown of cindr, the Drosophila ortholog of CD2AP, enhanced tau-induced neurodegeneration, implying CD2AP also participated in tau pathology. However, the role of rs9296559 in regulating Aβ and tau metabolism in AD was still unclear. MethodsHere, the associations of rs9296559 with CSF Aβ1–42, p-tau, and t-tau were performed using a linear regression model in a total of 543 cognitive normal (CN), mild cognitive impairment (MCI), and AD subjects from the Alzheimer’s disease Neuroimaging Initiative (ADNI) cohort. The results were replicated in an independent cohort consisting of 198 Chinese subjects recruited from our hospital. ResultsIn the ADNI cohort, CC + TC genotypes significantly increased CSF t-tau and p-tau levels in MCI patients but did not alter CSF tau levels in AD. This association was also observed in the replication cohort. Moreover, there was no association between rs9296559 and CSF Aβ1–42 level at different disease statuses in the two cohorts. ConclusionOur findings showed that rs9296559 was associated with higher CSF t-tau and p-tau levels in MCI, supporting that CD2AP modified AD risk by altering tau-related neurodegeneration in the early stage of the AD continuum. To the best of our knowledge, this is the first study to evaluate the association between CD2AP genotypes and AD CSF biomarkers.