Association of cerebrospinal fluid Aβ42 with A2M gene in cognitively normal subjects

Low cerebrospinal fluid (CSF) Aβ₄₂ levels correlate with increased brain Aβ deposition in Alzheimer's disease (AD), which suggests a disruption in the degradation and clearance of Aβ from the brain. In addition, APOE ε4 carriers have lower CSF Aβ₄₂ levels than non-carriers. The hypothesis of this investigation was that CSF Aβ₄₂ levels would correlate with regulatory region variation in genes that are biologically associated with degradation or clearance of Aβ from the brain. CSF Aβ₄₂ levels were tested for associations with Aβ degradation and clearance genes and APOE ε4. Twenty-four SNPs located within the 5′ and 3′ regions of 12 genes were analyzed. The study sample consisted of 99 AD patients and 168 cognitively normal control subjects. CSF Aβ₄₂ levels were associated with APOE ε4 status in controls but not in AD patients; A2M regulatory region SNPs were also associated with CSF Aβ₄₂ levels in controls but not in AD patients, even after adjusting for APOE ε4. These results suggest that genetic variation within the A2M gene influences CSF Aβ₄₂ levels.     

Induction of autoantibodies to glutamate in patients with Alzheimer’s disease

Autoantibodies to glutamate were found in blood plasma from patients with Alzheimer’s disease. The content of autoantibodies to glutamate in blood plasma from patients with moderate and severe dementia was 2-fold higher compared to patients with mild dementia. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 2, pp. 140–141, February, 2007     

Ginkgolide B inhibits the neurotoxicity of prions or amyloid-β1-42

Background  

Neuronal loss in Alzheimer's or prion diseases is preceded by the accumulation of fibrillar aggregates of toxic proteins (amyloid-β_1-42 or the prion protein). Since some epidemiological studies have demonstrated that the EGb 761 extract, from the leaves of the Ginkgo biloba tree, has a beneficial effect on Alzheimer's disease, the effect of some of the major components of the EGb 761 extract on neuronal responses to amyloid-β_1-42, or to a synthetic miniprion (sPrP106), were investigated.     

Valproic acid enhances microglial phagocytosis of amyloid-β1–42

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder manifested by memory loss, confusion and changes in mood. A principal pathology of this debilitating disorder is extracellular deposits of amyloid-β (Aβ) protein. The “amyloid hypothesis” postulates that a build-up of Aβ protein is responsible for neuronal loss and the ensuing symptoms of AD. One possible mechanism of Aβ clearance, and hence AD therapy, is phagocytosis of Aβ protein by microglial cells. Microglia are the brain's resident immune cells and phagocytosis is one of their innate functions. We are interested in identifying molecules that augment microglial-mediated phagocytosis of Aβ protein. We used the rodent BV-2 microglial cell line which readily phagocytose fluorescent latex beads and synthetic Aβ_1–42 peptide. BV-2 cells treated with the neuroactive drug valproic acid (VPA) showed greatly enhanced phagocytic activity for both latex beads and Aβ. VPA also reduced microglial viability by inducing apoptosis, as previously reported. The relevance of these in vitro results to the treatment of AD is unclear but further investigation into the effects of VPA on the clearance of Aβ through enhanced microglial phagocytosis is warranted.     

β-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis

Psychosis in Alzheimer disease differentiates a subgroup with more rapid decline, is heritable, and aggregates within families, suggesting a distinct neurobiology. Evidence indicates that greater impairments of cerebral cortical synapses, particularly in dorsolateral prefrontal cortex, may contribute to the pathogenesis of psychosis in Alzheimer disease (AD) phenotype. Soluble β-amyloid induces loss of dendritic spine synapses through impairment of long-term potentiation. In contrast, the Rho guanine nucleotide exchange factor (GEF) kalirin is an essential mediator of spine maintenance and growth in cerebral cortex. We therefore hypothesized that psychosis in AD would be associated with increased soluble β-amyloid and reduced expression of kalirin in the cortex. We tested this hypothesis in postmortem cortical gray matter extracts from 52 AD subjects with and without psychosis. In subjects with psychosis, the β-amyloid(1-42)/β-amyloid(1-40) ratio was increased, due primarily to reduced soluble β-amyloid(1-40), and kalirin-7, -9, and -12 were reduced. These findings suggest that increased cortical β-amyloid(1-42)/β-amyloid(1-40) ratio and decreased kalirin expression may both contribute to the pathogenesis of psychosis in AD.     

Functional roles of circular RNAs in Alzheimer’s disease

Although efforts have been made to develop therapeutic approaches, the clinical management of AD maintains a major challenge. CircRNAs are highly abundant and evolutionarily conserved in neuronal tissues in mammals. Accumulating data suggest that circRNAs regulate biological and pathological processes by sponging miRNAs, binding to RBPs, modulating mRNA stability, and being translated into peptides in various diseases, serving as biomarkers and potential therapeutic targets. Growing evidence demonstrates that circRNAs have been implicated in the pathogenesis of AD. Here, we summarized current studies on circRNAs involved in AD pathology, providing a theoretical basis for the use of circRNAs in AD treatment and diagnosis.     

The emerging role of exosomes in Alzheimer’s disease

Alzheimer’s disease (AD), manifested by memory loss and a decline in cognitive functions, is the most prevalent neurodegenerative disease accounting for 60–80 % of dementia cases. But, to-date, there is no effective treatment available to slow or stop the progression of AD. Exosomes are small extracellular vesicles that carry constituents, such as functional messenger RNAs, non-coding RNAs, proteins, lipids, DNA, and other bioactive substances of their source cells. In the brain, exosomes are likely to be sourced by almost all cell types and involve in cell communication to regulate cellular functions. The yet, accumulated evidence on the roles of exosomes and their constituents in the AD pathological process suggests their significance as additional biomarkers and therapeutic targets for AD. This review summarizes the current reported research findings on exosomes roles in the pathogenesis, diagnosis, and treatment of AD.     

The role of serotonin within the microbiota-gut-brain axis in the development of Alzheimer’s disease: A narrative review

Alzheimer’s disease (AD) is the most common cause of dementia, accounting for more than 50 million patients worldwide. Current evidence suggests the exact mechanism behind this devastating disease to be of multifactorial origin, which seriously complicates the quest for an effective disease-modifying therapy, as well as impedes the search for strategic preventative measures. Of interest, preclinical studies point to serotonergic alterations, either induced via selective serotonin reuptake inhibitors or serotonin receptor (ant)agonists, in mitigating AD brain neuropathology next to its clinical symptoms, the latter being supported by a handful of human intervention trials. Additionally, a substantial amount of preclinical trials highlight the potential of diet, fecal microbiota transplantations, as well as pre- and probiotics in modulating the brain’s serotonergic neurotransmitter system, starting from the gut. Whether such interventions could truly prevent, reverse or slow down AD progression likewise, should be initially tested in preclinical studies with AD mouse models, including sufficient analytical measurements both in gut and brain. Thereafter, its potential therapeutic effect could be confirmed in rigorously randomized controlled trials in humans, preferentially across the Alzheimer’s continuum, but especially from the prodromal up to the mild stages, where both high adherence to such therapies, as well as sufficient room for noticeable enhancement are feasible still. In the end, such studies might aid in the development of a comprehensive approach to tackle this complex multifactorial disease, since serotonin and its derivatives across the microbiota-gut-brain axis might serve as possible biomarkers of disease progression, next to forming a valuable target in AD drug development. In this narrative review, the available evidence concerning the orchestrating role of serotonin within the microbiota-gut-brain axis in the development of AD is summarized and discussed, and general considerations for future studies are highlighted.     

Alteration of the sialylation pattern and memory deficits by injection of Aβ(25–35) into the hippocampus of rats

Sialic acid in glycoconjugates participates in important cellular functions associated with normal development, growth, and communication. Therefore we evaluated the sialylation pattern and memory deficits caused by the injection of Aβ_(25–35) into the hippocampus (Hp) of rats. The eight-arm maze spatial-learning and memory test indicated that the injection of Aβ_(25–35) into subfield CA1 of the Hp impaired both learning and memory. The sialylation pattern was examined using sialic acid-specific lectins. Our results showed that Maackia amurensis agglutinin (MAA, specific for Neu5Acα2,3Gal) showed reactivity in the CA1 and dentate gyrus (DG) subfields of the Hp mainly in the group injected with vehicle, whereas Macrobrachium rosenbergii lectin (MRL, specific for Neu5,9,7Ac) and Sambucus nigra agglutinin (SNA, specific for Neu5Acα2,6Gal-GalNAc) had increased reactivity in the CA1 and DG subfields of the Hp in the Aβ_(25–35)-injected group. The staining pattern of the antibody specific for polysialic acid (a linear homopolymer of α-2,8-linked sialic acid) increased in the CA1 and DG subfields of the Hp of the Aβ_(25–35) group compared to the control group. Our results suggest that injection of Aβ_(25–35) causes impairment in spatial memory and alters the sialylation pattern in response to compensatory reorganization and-or sprouting of dendrites and axons of the surviving neurons.     

Involvement of WAVE Accumulation in Aβ/APP Pathology-Dependent Tangle Modification in Alzheimer’s Disease

Synaptic deficits are closely correlated with cognitive dysfunction in Alzheimer’s disease (AD), and synaptic integrity is regulated by the actin cytoskeleton. We demonstrated here that the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE), a key molecule for actin assembly, co-aggregated with both hyperphosphorylated tau and phosphorylated collapsin response mediator protein 2 (CRMP2) in neurofibrillary tangles and abnormal neurites of the AD brain. Although phosphorylated CRMP2 accumulation was induced in the brains of JNPL3 mice, WAVE accumulation was not detected in the brains of either JNPL3 or Tg2576 mice that developed neurofibrillary tangles and amyloid-β (Aβ) plaques, respectively. Interestingly, both phosphorylated CRMP2 accumulation and WAVE accumulation were recapitulated in the brains of 3xTg-AD mice that developed neurofibrillary tangles and Aβ plaques. In addition, we found an interaction between WAVE, CRMP2, and hyperphosphorylated tau in the cytosolic fraction of the AD brain. Taken together, WAVE accumulation may require both Aβ/amyloid precursor protein and tau pathologies, and an interaction between WAVE, CRMP2, and hyperphosphorylated tau may be involved in this process. Thus, WAVE accumulation may be involved in Aβ/amyloid precursor protein mediated-tangle modification, suggesting a possible correlation between WAVE accumulation and synaptic deficits induced by disturbances in actin assembly in AD brains.The pathological hallmarks of Alzheimer’s disease (AD) include senile plaques, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration.¹ Senile plaques are formed by the accumulation of extracellular amyloid-β (Aβ), which is generated from the amyloid precursor protein (APP), and NFTs are composed of paired helical filaments (PHFs) in neuronal perikarya. Minute bundles of PHFs are found in dendrites as neuropil threads (curly fibers) and in axonal terminals as dystrophic neurites surrounding senile plaques. The main component of PHFs has been identified as abnormally hyperphosphorylated tau protein.² Tau is a microtubule-associated protein; therefore, one component in the developmental cascade of AD may include a disturbance of microtubule cytoskeleton.³The formation of abnormal neurites such as neuropil threads and dystrophic neurites in AD brains is associated with aberrant neuritic sprouting.⁴ Neuritic sprouting is critically dependent on the interplay between microtubule and actin cytoskeletons.⁵ Furthermore, synaptic integrity is maintained by the precise formation of dendritic spines that are major sites of synaptic contacts, and the formation is structurally regulated by the actin cytoskeleton.⁶ On the other hand, progressive synaptic dysfunction is found in AD brains and closely correlates with cognitive deficits.⁷ Thus, the disruption of the actin cytoskeleton, as well as the disturbance of microtubule assembly are suggested to be involved in the developmental cascade in AD. However, the relationship between disruptions of microtubule and actin cytoskeletons and the involvement of Aβ/APP and tau pathologies in actin cytoskeletal disturbance in AD remain poorly understood.Recently, Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE) has been identified as a key molecule for actin assembly,⁸ and WAVE knockout mice demonstrated the association between WAVE dysfunction and impaired learning and memory.^9,10 In addition, collapsin response mediator protein 2 (CRMP2) regulates microtubule assembly in neurons.¹¹ A recent study has reported that CRMP2 interacts with the specifically Rac1-associated protein 1/WAVE complex, and transports WAVE into the axonal growth cones.¹² Thus, CRMP2 and WAVE seem to be mediators required in the cross talk between microtubule and actin cytoskeletons. Previous studies have demonstrated that CRMP2 is highly phosphorylated and is associated with NFTs and abnormal neurites in AD brains.^13,14 In this context, the abnormality of CRMP2 possibly influences the property of WAVE and furthermore actin assembly.     

β-amyloid oligomers and cellular prion protein in Alzheimer’s disease

Prefibrillar oligomers of the β-amyloid peptide (Aβ) are recognized as potential mediators of Alzheimer’s disease (AD) pathophysiology. Deficits in synaptic function, neurotoxicity, and the progression of AD have all been linked to the oligomeric Aβ assemblies rather than to Aβ monomers or to amyloid plaques. However, the molecular sites of Aβ oligomer action have remained largely unknown. Recently, the cellular prion protein (PrP^C) has been shown to act as a functional receptor for Aβ oligomers in brain slices. Because PrP^C serves as the substrate for Creutzfeldt–Jakob Disease (CJD), these data suggest mechanistic similarities between the two neurodegenerative diseases. Here, we review the importance of Aβ oligomers in AD, commonalities between AD and CJD, and the newly emergent role of PrP^C as a receptor for Aβ oligomers.     

Similar promotion of Aβ1-42 fibrillogenesis by native apolipoprotein E ε3 and ε4 isoforms

The apolipoprotein E ε4 allele contributes to the genetic susceptibility underlying a large proportion (~40–60%) of typical, sporadic Alzheimer disease. Apolipoprotein E deficient mice made transgenic for human apolipoprotein E ε4 accumulate excess cerebral amyloid when compared to similarly prepared mice expressing human apolipoprotein E ε3. Therefore, it is important to search for relevant interactions(s) between apolipoprotein E ε4 and Aβ in order to clarify the biological role for apolipoprotein E ε4 in Alzheimer disease. Using a thioflavine T (ThT)-based assay, we have investigated the effects of native human apolipoprotein E isoforms on the kinetics of Aβ fibrillogenesis. No obvious profibrillogenic activity was detected in Aβ_1-40-based assays of any native apolipoprotein E isoform. However, when ThT assays were repeated using Aβ_1-42, modest, but statistically significant, profibrillogenic activity was detected in both apolipoprotein E ε3- and apolipoprotein E ε4-containing media and was similar in magnitude for the two isoforms. These data demonstrate that native apolipoprotein E possesses "pathological chaperone"-type activity for Aβ: in other words, the data indicate that a chaperone-like misfolding reaction can occur between native apolipoprotein E and Aβ. However, the equipotent activities of the apolipoprotein E ε3 and ε4 isoforms suggests the possibility that either extended co-incubation of apolipoprotein E and Aβ, or, perhaps, the inclusion in the reaction of other fibrillogenesis-modulation co-factors (such as metal ions, or inflammatory mediators such as reactive oxygen species, α₂-macroglobulin, apolipoprotein J, etc.) may be required for modeling in vitro the apolipoprotein E-isoform-specific-regulation of extracellular Aβ accumulation that occurs in vivo. Alternatively, other events, such as differential apolipoprotein E-isoform-mediated clearance of Aβ or of apolipoprotein E/Aβ complexes may underlie apolipoprotein E-isoform-dependent Aβ accumulation.     

Disturbed assembly of human cerebral microtubules in Alzheimer’s disease

It is shown for the first time that microtubular proteins isolated from the brain of patients with Alzheimer’s disease can in vitro polymerize into microtubules with abnormal structure. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 2, pp. 229–233, February, 2006     

有氧运动干预Aβ1-42诱导阿尔茨海默病大鼠海马突触结构与突触蛋白的改变

背景：β-淀粉样蛋白(Aβ)在海马中的积累和沉积会影响突触形态和功能,导致突触可塑性受损,后者被认为是阿尔茨海默病学习记忆缺陷的根本原因。有氧运动能否减轻淀粉样蛋白诱导的突触受损从而改善阿尔茨海默病患者的学习记忆能力尚不清楚。目的：观察有氧运动对Aβ_1-42诱导阿尔茨海默病大鼠海马突触结构与突触标志性蛋白突触素、突触后致密物95表达的影响,探讨有氧运动对阿尔茨海默病学习记忆能力影响的机制。方法：将80只SD大鼠随机分为4组,即生理盐水对照组、生理盐水运动组、Aβ_1-42诱导模型组以及Aβ_1-42运动组,每组20只。其中后两组大鼠双侧海马注入10μL Aβ_1-42(1μg/μL),前两组大鼠双侧海马注入10μL生理盐水。Aβ_1-42/生理盐水注射后第2天,生理盐水运动组和Aβ_1-42运动组开始进行有氧运动训练,持续5周,每周运动6 d。采用Morris水迷宫实验检测大鼠学习记忆能力,然后取脑组织,采用电镜技术及免疫荧光、Western blot技术分别检测大...     

Influence of genetic and cardiometabolic risk factors in Alzheimer’s disease

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder. Cardiometabolic and genetic risk factors play an important role in the trajectory of AD. Cardiometabolic risk factors including diabetes, mid-life obesity, mid-life hypertension and elevated cholesterol have been linked with cognitive decline in AD subjects. These potential risk factors associated with cerebral metabolic changes which fuel AD pathogenesis have been suggested to be the reason for the disappointing clinical trial results. In appreciation of the risks involved, using search engines such as PubMed, Scopus, MEDLINE and Google Scholar, a relevant literature search on cardiometabolic and genetic risk factors in AD was conducted. We discuss the role of genetic as well as established cardiovascular risk factors in the neuropathology of AD. Moreover, we show new evidence of genetic interaction between several genes potentially involved in different pathways related to both neurodegenerative process and cardiovascular damage.     

Downregulated miR-29c correlates with increased BACE1 expression in sporadic Alzheimer’s disease

Background: Beta-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) is conceived as a potential target for therapies against Alzheimer disease (AD) which is characterized by the accumulation of plaques formed of short β-amyloid (APPβ) peptides. Recently, such microRNAs, as miR-29a, miR-29b-1 have been shown to correlate with abnormally high levels of BACE1 and APPβ in sporadic AD. Methods: In order to confirm whether miR-29c correlates with the BACE1 upregulation in sporadic AD, we firstly evaluated the expression of miR-29c and BACE1, the APPβ accumulation in sporadic AD brain tissues and analyzed the correlation of miR-29c with BACE1. Then we determined the regulation of miR-29c in human heuroblastoma SH-SY5Y cells on the BACE1 expression and APPβ accumulation. And finally we determined the targeting to 3’ UTR of BACE1 by miR-29c by a luciferase reporter. Results: It was demonstrated that miR-29c was downregulated in sporadic AD brains, in an association with an upregulation of BACE1 in both mRNA and protein level of BACE1, and also an elevated APPβ accumulation. And the manipulated high level of miR-29c with miR-29c mimics transfection significantly reduced the protein level of BACE1 and APPβ accumulation in human neuroblastoma SH-SY5Y cells. Further luciferase reporter assay demonstrated that miR-29c targets the 3’ UTR of BACE1 and downregulated the BACE1 in HEK293 cells. Conclusion: Present study indicated that miR-29c was downregulated in sporadic AD brains, and it targeted the 3’ UTR of BACE1, reduced the BACE1 expression, and downregulated the APPβ accumulation in vitro.