LRRK2 Kinase Inhibition Attenuates Astrocytic Activation in Response to Amyloid β Fibrils.

Intracerebral accumulation of amyloid-β in the extracellular plaques of Alzheimer's disease (AD) brains represents the main cause of reactive astrogliosis and neuroinflammatory response. Of relevance, leucine-rich repeat kinase 2 (LRRK2), a kinase linked to genetic and sporadic Parkinson's disease (PD), has been identified as a positive mediator of neuroinflammation upon different inflammatory stimuli, however its pathogenicity in AD remains mainly unexplored. In this study, by using pharmacological inhibition of LRRK2 and murine primary astrocytes, we explored whether LRRK2 regulates astrocytic activation in response to amyloid-β (Aβ).

The potential convergence of NLRP3 inflammasome, potassium, and dopamine mechanisms in Parkinson's disease.

The pathology of Parkinson's disease (PD) is characterized by α-synuclein aggregation, microglia-mediated neuroinflammation, and dopaminergic neurodegeneration in the substantia nigra with collateral striatal dopamine signaling deficiency. Microglial NLRP3 inflammasome activation has been linked independently to each of these facets of PD pathology. The voltage-gated potassium channel Kv1.

Dopamine signaling modulates microglial NLRP3 inflammasome activation: implications for Parkinson's disease.

Background: Parkinson's disease (PD) is characterized by the loss of nigral dopaminergic neurons leading to impaired striatal dopamine signaling, α-synuclein- (α-syn-) rich inclusions, and neuroinflammation. Degenerating neurons are surrounded by activated microglia with increased secretion of interleukin-1β (IL-1β), driven largely by the NLRP3 inflammasome. A critical role for microglial NLRP3 inflammasome activation in the progression of both dopaminergic neurodegeneration and α-syn pathology has been demonstrated in parkinsonism mouse models.

Inflammation and Cognitive Functioning in Depressed Older Adults Treated With Electroconvulsive Therapy: A Prospective Cohort Study.

Despite the effectiveness of electroconvulsive therapy (ECT), patients and practitioners are often reluctant to start it due to the risk of transient cognitive side effects, particularly in older patients. Inflammatory processes may be associated with the occurrence of these effects. This study assessed whether inflammatory markers prior to ECT are associated with cognitive functioning in depressed patients treated with ECT.

The pattern of inflammatory markers during electroconvulsive therapy in older depressed patients.

Objectives: An association is found between changes in cytokine levels and antidepressant treatment outcome. Also, a proinflammatory profile is associated with a favourable electroconvulsive therapy (ECT) outcome. This paper investigates the pattern of inflammatory markers during a course of ECT in older depressed patients and whether this pattern is associated with ECT outcome.

α-Synuclein evokes NLRP3 inflammasome-mediated IL-1β secretion from primary human microglia.

Synucleinopathies such as Parkinson's disease (PD) are hallmarked by α-synuclein (α-syn) pathology and neuroinflammation. This neuroinflammation involves activated microglia with increased secretion of interleukin-1β (IL-1β). The main driver of IL-1β secretion from microglia is the NLRP3 inflammasome.

APOE ε4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease.

Background: Aggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer's disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) ε4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid β aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE ε4 genotype.

Impaired Innate Immunity Mechanisms in the Brain of Alzheimer's Disease.

Among environmental factors likely associated with Alzheimer's disease (AD), persistent virus infections, and age-related progressive decline of immune competence might play a pivotal role. However, AD antimicrobial brain immune responses are poorly investigated. The present study focused on genes involved in antimicrobial defenses, especially against virus infections, in the AD brain.

S100 calcium-binding protein B in older patients with depression treated with electroconvulsive therapy.

Background: Increasing evidence suggests that glial mediated disruption of neuroplasticity contributes to depression. S100 calcium-binding protein B (S100B) promotes neuronal protection in nanomolar concentrations. Studies on its possible role as a treatment outcome marker in affective disorders are limited.

Decoration of Fibrin with Extracellular Chaperones.

Background: Many proteins bind to fibrin during clot formation in plasma. We previously identified by mass spectrometry the most abundant proteins that noncovalently bind to fibrin clots. Several of these proteins (e.

Inflammation and remission in older patients with depression treated with electroconvulsive therapy; findings from the MODECT study.

Background: Compelling evidence links elevated levels of C-reactive protein (CRP) and other inflammatory markers to poor treatment outcome of antidepressant medication. Little is known about the contribution of low-grade inflammation to treatment response to electroconvulsive therapy (ECT) in severely depressed patients.

Method: Associations between serum levels of CRP, interleukin-6, interleukin-10, and tumour necrosis factor-α as well as remission of depression, time to remission, and speed of decline of depressive symptoms were examined in 95 older (mean age: 73.

ApoE and clusterin CSF levels influence associations between APOE genotype and changes in CSF tau, but not CSF Aβ42, levels in non-demented elderly.

Apolipoprotein E (APOE) ε4 genotype is associated with increased cerebral amyloid beta (Aβ) deposition in nondemented elderly and suggested to influence ApoE as well as ApoJ (clusterin [Clu]) and ApoA1 expression. We aimed to assess whether APOE affects early Alzheimer's disease pathophysiology via these apolipoproteins. Cerebrospinal fluid (CSF) ApoE, Clu, ApoA1, and CSF amyloid beta (Aβ42) and tau levels were assessed in 403 individuals with subjective cognitive decline and mild cognitive impairment using enzyme-linked immunosorbent assay.

Aβ-oligomer uptake and the resulting inflammatory response in adult human astrocytes are precluded by an anti-Aβ single chain variable fragment in combination with an apoE mimetic peptide.

An imbalance between production and clearance of soluble amyloid-β (Aβ) initiates the pathological process in sporadic Alzheimer's disease (AD). Aβ-specific antibodies seemed promising as therapeutic option in AD mouse models. In patients, however, vascular side-effects and Aβ-antibody complex-induced microglial and/or perivascular macrophage inflammatory responses were encountered.

Effects of an Aβ-antibody fragment on Aβ aggregation and astrocytic uptake are modulated by apolipoprotein E and J mimetic peptides.

Aβ-Immunotherapy has long been studied in the treatment of Alzheimer's disease (AD), but not how other molecules involved in the disease can affect antibody performance. We previously designed an antibody fragment, scFv-h3D6, and showed that it precludes Aβ-induced cytotoxicity by withdrawing Aβ oligomers from the amyloid pathway towards a non-toxic, worm-like pathway. ScFv-h3D6 was effective at the behavioral, cellular, and molecular levels in the 3xTg-AD mouse model.

Apolipoprotein A1 in Cerebrospinal Fluid and Plasma and Progression to Alzheimer's Disease in Non-Demented Elderly.

Background: HDL-cholesterol transporter Apolipoprotein A1 (ApoA1) holds neuroprotective properties, such as inhibition of amyloid-β aggregation. Low plasma ApoA1 concentrations are associated with Alzheimer's disease (AD). Little is known about ApoA1 levels in the pre-dementia stages of AD.

Facilitating the Validation of Novel Protein Biomarkers for Dementia: An Optimal Workflow for the Development of Sandwich Immunoassays.

Different neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), lead to dementia syndromes. Dementia will pose a huge impact on society and thus it is essential to develop novel tools that are able to detect the earliest, most sensitive, discriminative, and dynamic biomarkers for each of the disorders. To date, the most common assays used in large-scale protein biomarker analysis are enzyme-linked immunosorbent assays (ELISA), such as the sandwich immunoassays, which are sensitive, practical, and easily implemented.

Clusterin Levels in Plasma Predict Cognitive Decline and Progression to Alzheimer's Disease.

Background: Increased clusterin levels have been reported in brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients. Because changes are also observed in mild cognitive impairment (MCI), a possible relationship between clusterin levels and early neurodegenerative changes in AD was suggested.

Objectives: To determine whether clusterin concentrations could 1) serve as a diagnostic marker for AD, 2) predict disease progression in MCI, and 3) correlate with AD-biomarkers.

Amyloid-β oligomers relate to cognitive decline in Alzheimer's disease.

Background: Amyloid-β (Aβ)-oligomers are neurotoxic isoforms of Aβ and are a potential diagnostic biomarker for Alzheimer's disease (AD).

Objectives: 1) Analyze the potential of Aβ-oligomer concentrations in cerebrospinal fluid (CSF) to diagnose and predict progression to AD in a large clinical study sample. 2) Monitor Aβ-oligomer concentrations over-time, both in early and advanced stages of AD.

BRI2-BRICHOS is increased in human amyloid plaques in early stages of Alzheimer's disease.

BRI2 protein binds amyloid precursor protein to halt amyloid-β production and inhibits amyloid-β aggregation via its BRICHOS-domain suggesting a link between BRI2 and Alzheimer's disease (AD). Here, we investigate the possible involvement of BRI2 in human AD pathogenesis. BRI2 containing BRICHOS-domain was increased up to 3-fold in AD hippocampus (p = 0.

Apolipoproteins E and J interfere with amyloid-beta uptake by primary human astrocytes and microglia in vitro.

Defective clearance of the amyloid-β peptide (Aβ) from the brain is considered a strong promoter in Alzheimer's disease (AD) pathogenesis. Astrocytes and microglia are important mediators of Aβ clearance and Aβ aggregation state and the presence of amyloid associated proteins (AAPs), such as Apolipoproteins E and J (ApoE and ApoJ), may influence Aβ clearance by these cells. Here we set out to investigate whether astrocytes and microglia differ in uptake efficiency of Aβ oligomers (Aβoligo ) and Aβ fibrils (Aβfib ), and whether the Aβ aggregation state and/or presence of AAPs affect Aβ uptake in these cells in vitro.

Complement activation by ceramide transporter proteins.

C1q is the initiator of the classical complement pathway and, as such, is essential for efficient opsonization and clearance of pathogens, altered self-structures, and apoptotic cells. The ceramide transporter protein (CERT) and its longer splicing isoform CERTL are known to interact with extracellular matrix components, such as type IV collagen, and with the innate immune protein serum amyloid P. In this article, we report a novel function of CERT in the innate immune response.

NG2 cells, a new trail for Alzheimer's disease mechanisms?

Background: Neuron Glial 2 (NG2) cells are glial cells known to serve as oligodendrocyte progenitors as well as modulators of the neuronal network. Altered NG2 cell morphology and up-regulation as well as increased shedding of the proteoglycan NG2 expressed on the cell surface have been described in rodent models of brain injury. Here we describe alterations in the human NG2 cell population in response to pathological changes characteristic of Alzheimer's disease (AD).

Quantification of clusterin in paired cerebrospinal fluid and plasma samples.

Background: Clusterin (ApoJ) is an amyloid-associated protein and plays an important role in Alzheimer's disease (AD) pathology. Recent genome-wide association studies have indicated that certain genetic variants increase the risk of developing AD. To determine if the expression of clusterin is different in AD patients, both systemically and locally in the brain, differs between (subgroups of) AD patients and non-AD cases, an assay available that detects clusterin in both plasma and cerebrospinal fluid (CSF) with equal sensitivity would be helpful.

ATP-binding cassette transporters P-glycoprotein and breast cancer related protein are reduced in capillary cerebral amyloid angiopathy.

Alzheimer's disease (AD) is the most common form of dementia and marked by deposition of amyloid-β (Aβ) within the brain. Alterations of Aβ transporters at the neurovasculature may play a role in the disease process. We investigated the expression of ABC transporters P-glycoprotein (P-gp) and breast cancer related protein (BCRP) in non-neurologic controls, AD, and severe capillary cerebral amyloid angiopathy (capCAA) cases, which are characterized by deposition of Aβ within cerebral capillaries.

Cerebrospinal fluid and plasma clusterin levels in Parkinson's disease.

Clusterin is a multifunctional chaperone protein that has repeatedly been linked to Alzheimer's disease (AD) pathogenesis and, more recently, also to Parkinson's disease (PD) by both genetic and proteomic analyses. Although clusterin is detectable in cerebrospinal fluid (CSF) and plasma, studies comparing clusterin levels in PD patients and controls have been scarce and yielded conflicting data. The aim of the present study was to determine whether CSF and/or plasma clusterin levels differ between PD patients and controls and are related to disease severity.